Substituted Pyrrolidines and Methods of Use

ABSTRACT

wherein R1, R2, R2A, R3, R3A, R4, and R5 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/723,896 filed on Oct. 3, 2017, which claims priority to U.S.Provisional Application No. 62/405,562, filed Oct. 7, 2016, all of whichare incorporated herein in their entirety for all purposes.

BACKGROUND OF THE INVENTION Technical Field

The invention relates to substituted pyridine compounds that aremodulators of the Cystic Fibrosis Transmembrane Conductance Regulator(CFTR) protein, useful in treating diseases and conditions mediated andmodulated by CFTR. The invention also relates to compositions containingcompounds of the invention, processes for their preparation, and methodsof treatment using them.

Description of Related Technology

ABC transporters are a family of homologous membrane transporterproteins regulating the transport of a wide variety of pharmacologicalagents (for example drugs, xenobiotics, anions, etc.) that bind and usecellular adenosine triphosphate (ATP) for their specific activities.Some of these transporters were found to defend malignant cancer cellsagainst chemotherapeutic agents, acting as multidrug resistance proteins(like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP1). So far, 48 ABC transporters, grouped into 7 families based on theirsequence identity and function, have been identified.

ABC transporters provide protection against harmful environmentalcompounds by regulating a variety of important physiological roleswithin the body, and therefore represent important potential drugtargets for the treatment of diseases associated with transporterdefects, outwards cell drug transport, and other diseases in whichmodulation of ABC transporter activity may be beneficial.

The cAMP/ATP-mediated anion channel, CFTR, is one member of the ABCtransporter family commonly associated with diseases, which is expressedin a variety of cell types, including absorptive and secretory epitheliacells, where it regulates anion flux across the membrane, as well as theactivity of other ion channels and proteins. The activity of CFTR inepithelial cells is essential for the maintenance of electrolytetransport throughout the body, including respiratory and digestivetissue (Quinton, P. M., 1990. Cystic fibrosis: a disease in electrolytetransport. FASEB J. 4, 2709-2717).

The gene encoding CFTR has been identified and sequenced (Kerem, B.,Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K.,Chakravarti, A., Buchwald, M., Tsui, L. C., 1989. Identification of thecystic fibrosis gene: genetic analysis. Science 245, 1073-1080). CFTRcomprises about 1480 amino acids that encode a protein made up of atandem repeat of transmembrane domains, each containing sixtransmembrane helices and a nucleotide binding domain. The pair oftransmembrane domains is linked by a large, polar, regulatory (R)-domainwith multiple phosphorylation sites that regulate channel activity andcellular trafficking.

Cystic fibrosis (CF) is caused by a defect in this gene which inducesmutations in CFTR. Cystic fibrosis is the most common fatal geneticdisease in humans, and affects ˜0.04% of white individuals (Bobadilla,J. L., Macek, M., Jr, Fine, J. P., Farrell, P. M., 2002. Cysticfibrosis: a worldwide analysis of CFTR mutations—correlation withincidence data and application to screening. Hum. Mutat. 19, 575-606.doi: 10.1002/humu.10041), for example, in the United States, about onein every 2,500 infants is affected, and up to 10 million people carry asingle copy of the defective gene without apparent ill effects; moreoversubjects bearing a single copy of the gene exhibit increased resistanceto cholera and to dehydration resulting from diarrhea. This effect mightexplain the relatively high frequency of the CF gene within thepopulation.

In contrast, individuals with two copies of the CF associated genesuffer from the debilitating and fatal effects of CF, including chroniclung infections.

In cystic fibrosis patients, mutations in endogenous respiratoryepithelial CFTR fails to confer chloride and bicarbonate permeability toepithelial cells in lung and other tissues, thus leading to reducedapical anion secretion and disruptions of the ion and fluid transport.This decrease in anion transport causes an enhanced mucus and pathogenicagent accumulation in the lung triggering microbial infections thatultimately cause death in CF patients.

Beyond respiratory disease, CF patients also suffer fromgastrointestinal problems and pancreatic insufficiency that result indeath if left untreated. Furthermore, female subjects with cysticfibrosis suffer from decreased fertility, whilst males with cysticfibrosis are infertile.

A variety of disease causing mutations has been identified throughsequence analysis of the CFTR gene of CF chromosomes (Kerem, B.,Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K.,Chakravarti, A., Buchwald, M., Tsui, L. C., 1989. Identification of thecystic fibrosis gene: genetic analysis. Science 245, 1073-1080).F508delCFTR, the most common CF mutation (present in at least 1 allelein ˜90% of CF patients) and occurring in approximately 70% of the casesof cystic fibrosis, contains a single amino acid deletion ofphenylalanine 508. This deletion prevents the nascent protein fromfolding correctly, which protein in turn cannot exit the endoplasmicreticulum (ER) and traffic to the plasma membrane, and then is rapidlydegraded. As a result, the number of channels present in the membrane isfar less than in cells expressing wild-type CFTR. In addition toimpaired trafficking, the mutation results in defective channel gating.Indeed, even if F508delCFTR is allowed to reach the cell plasma membraneby low-temperature (27° C.) rescue where it can function as acAMP-activated chloride channel, its activity is decreased significantlycompared with WT-CFTR (Pasyk, E. A., Foskett, J. K., 1995. Mutant(F508delCTFR) Cystic Fibrosis Transmembrane Conductance Regulator Cl⁻channel is functional when retained in Endoplasmic Reticulum ofmammalian cells. J. Biol. Chem. 270, 12347-12350).

Other mutations with lower incidence have also been identified thatalter the channel regulation or the channel conductance. In case of thechannel regulation mutants, the mutated protein is properly traffickedand localized to the plasma membrane but either cannot be activated orcannot function as a chloride channel (e.g. missense mutations locatedwithin the nucleotide binding domains), examples of these mutations areG551D, G178R, and G1349D. Mutations affecting chloride conductance havea CFTR protein that is correctly trafficked to the cell membrane butthat generates reduced chloride flow (e.g. missense mutations locatedwithin the membrane-spanning domain), examples of these mutations areR117H and R334W.

In addition to cystic fibrosis, CFTR activity modulation may bebeneficial for other diseases not directly caused by mutations in CFTR,such as, for example, chronic obstructive pulmonary disease (COPD), dryeye disease, and Sjögren's syndrome.

COPD is characterized by a progressive and non-reversible airflowlimitation, which is due to mucus hypersecretion, bronchiolitis, andemphysema. A potential treatment of mucus hypersecretion and impairedmucociliary clearance that is common in COPD could consist in usingactivators of mutant or wild-type CFTR. In particular, the anionsecretion increase across CFTR may facilitate fluid transport into theairway surface liquid to hydrate the mucus and optimize periciliaryfluid viscosity. The resulting enhanced mucociliary clearance would helpin reducing the symptoms associated with COPD.

Dry eye disease is characterized by a decrease in tear production andabnormal tear film lipid, protein and mucin profiles. Many factors maycause dry eye disease, some of which include age, arthritis, Lasik eyesurgery, chemical/thermal burns, medications, allergies, and diseases,such as cystic fibrosis and Sjögren's syndrome. Increasing anionsecretion via CFTR could enhance fluid transport from the cornealendothelial cells and secretory glands surrounding the eye, andeventually improve corneal hydration, thus helping to alleviate dry eyedisease associated symptoms. Sjögren's syndrome is an autoimmune diseasewhere the immune system harms moisture-producing glands throughout thebody, including the eye, mouth, skin, respiratory tissue, liver, vagina,and gut. The ensuing symptoms, include, dry eye, mouth, and vagina, aswell as lung disease. Sjögren's syndrome is also associated withrheumatoid arthritis, systemic lupus, systemic sclerosis, andpolymyositis/dermatomyositis. The cause of the disease is believed tolie in defective protein trafficking, for which treatment options arelimited. As a consequence, modulation of CFTR activity may helphydrating the various organs and help to elevate the associatedsymptoms.

In addition to CF, the defective protein trafficking induced by the508delCFTR has been shown to be the underlying basis for a wide range ofother diseases, in particular diseases where the defective functioningof the endoplasmic reticulum (ER) may either prevent the CFTR protein toexit the cell, and/or the misfolded protein is degraded (Morello, J.-P.,Bouvier, M., Petäjä-Repo, U. E., Bichet, D. G., 2000. Pharmacologicalchaperones: a new twist on receptor folding. Trends Pharmacol. Sci. 21,466-469. doi: 10.1016/S0165-6147(00)01575-3; Shastry, B. S., 2003.Neurodegenerative disorders of protein aggregation. Neurochem. Int. 43,1-7. doi:10.1016/S0197-0186(02)00196-1; Zhang, W., Fujii, N., Naren, A.P., 2012. Recent advances and new perspectives in targeting CFTR fortherapy of cystic fibrosis and enterotoxin-induced secretory diarrheas.(Future Med. Chem. 4, 329-345. doi:10.4155/fmc.12.1).

A number of genetic diseases are associated with a defective ERprocessing equivalent to the defect observed with CFTR in CF such asglycanosis CDG type 1, hereditary emphysema (α-1-antitrypsin (PiZvariant)), congenital hyperthyroidism, osteogenesis imperfecta (Type I,II, or IV procollagen), hereditary hypofibrinogenemia (fibrinogen), ACTdeficiency (α-1-antichymotrypsin), diabetes insipidus (DI),neurohypophyseal DI (vasopressin hormoneN2-receptor), nephrogenic DI(aquaporin II), Charcot-Marie Tooth syndrome (peripheral myelin protein22), Pelizaeus-Merzbacher disease, neurodegenerative diseases such asAlzheimer's disease (APP and presenilins), Parkinson's disease,amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick'sdisease, several polyglutamine neurological disorders such asHuntington's disease, spinocerebellar ataxia type I, spinal and bulbarmuscular atrophy, dentatorubral pallidoluysian, and myotonic dystrophy,as well as spongiform encephalopathies, such as hereditaryCreutzfeldt-Jakob disease (prion protein processing defect), Fabrydisease (lysosomal α-galactosidase A), Straussler-Scheinker syndrome,chronic obstructive pulmonary disease (COPD), dry eye disease, andSjögren's syndrome.

In addition to up-regulation of the activity of CFTR, anion secretionreduction by CFTR modulators may be beneficial for the treatment ofsecretory diarrheas, in which epithelial water transport is dramaticallyincreased as a result of secretagogue activated chloride transport. Themechanism involves elevation of cAMP and stimulation of CFTR.

Regardless of the cause, excessive chloride transport is seen in alldiarrheas, and results in dehydration, acidosis, impaired growth anddeath. Acute and chronic diarrheas remain a major medical problemworldwide, and are a significant factor in malnutrition, leading todeath in children of less than five years old (5,000,000 deaths/year).Furthermore, in patients with chronic inflammatory bowel disease (IBD)and/or acquired immunodeficiency syndrome (AIDS), diarrhea is adangerous condition.

Accordingly, there is a need for novel compounds able to modulate CFTR.In particular, the present invention discloses compounds that may act asCFTR modulators for the treatment of cystic fibrosis. The presentinvention also provides methods for the preparation of these compounds,pharmaceutical compositions comprising these compounds and methods forthe treatment of cystic fibrosis by administering the compounds of theinvention.

SUMMARY

In one aspect, the invention provides for compounds of Formula (I)

-   -   wherein    -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof;    -   R^(2A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein the R³        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³        C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I; and    -   R^(3A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, and C₁-C₆ haloalkyl; or    -   R³ and R^(3A), together with the carbon to which they are        attached, form a C₃-C₆ cycloalkyl; wherein the C₃-C₆ cycloalkyl        formed from R³ and R^(3A) and the carbon to which they are        attached is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I;    -   R⁴ is selected from the group consisting of L¹-C₆-C₁₀ aryl,        L¹-5-11 membered heteroaryl, L¹-4-12 membered heterocyclyl,        L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl; wherein the R⁴        C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 membered        heterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH,        oxo, CN, NO₂, F, Cl, Br and I;    -   L¹ is absent, or is selected from the group consisting of C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆        alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene,        and C₂-C₆ alkynylene, alone or as part of a group, are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, OH, and oxo;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, 4-6 membered monocyclic        heterocycle fused to a phenyl group, C₃-C₁₁ cycloalkyl, and        C₄-C₁₁ cycloalkenyl; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11        membered heteroaryl, 4-6 membered monocyclic heterocycle fused        to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br        and I; wherein the R⁶ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸,        NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R²¹, OR²¹,        C(O)R²¹, OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH,        oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,        C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and        5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6        membered heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,        N(C₁-C₆ alkyl)₂, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R⁵, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹⁵ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo,        OH, CN, NO₂, F, Cl, Br and I;    -   R¹⁶ and R¹⁷, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁸, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl,        Br and I;    -   R¹⁹ and R²⁰, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I;    -   R²² and R²³, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy-        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; and    -   R²⁵ and R²⁶, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl.

Another aspect of the invention relates to pharmaceutical compositionscomprising a compound of the invention, and a pharmaceutical carrier.Such compositions can be administered in accordance with a method of theinvention, typically as part of a therapeutic regimen for treatment orprevention of conditions and disorders related to Cystic FibrosisTransmembrane Conductance Regulator activity. In a particular aspect,the pharmaceutical compositions may additionally comprise furthertherapeutically active ingredients suitable for use in combination withthe compounds of the invention. In a more particular aspect, the furthertherapeutically active ingredient is an agent for the treatment ofcystic fibrosis.

Moreover, the compounds of the invention, useful in the pharmaceuticalcompositions and treatment methods disclosed herein, arepharmaceutically acceptable as prepared and used.

Yet another aspect of the invention relates to a method for treating, orpreventing conditions and disorders related to Cystic FibrosisTransmembrane Conductance Regulator activity in mammals. Moreparticularly, the method is useful for treating or preventing conditionsand disorders related to cystic fibrosis, Sjögren's syndrome, pancreaticinsufficiency, chronic obstructive lung disease, or chronic obstructiveairway disease. Accordingly, the compounds and compositions of theinvention are useful as a medicament for treating or preventing CysticFibrosis Transmembrane Conductance Regulator modulated disease.

The compounds, compositions comprising the compounds, methods for makingthe compounds, and methods for treating or preventing conditions anddisorders by administering the compounds are further described herein.

In a particular aspect, the compounds of the invention are provided foruse in the treatment of cystic fibrosis. In a particular aspect, thecompounds of the invention are provided for use in the treatment ofcystic fibrosis caused by class I, II, III, IV, V, and/or VI mutations.

The present invention also provides pharmaceutical compositionscomprising a compound of the invention, and a suitable pharmaceuticalcarrier for use in medicine. In a particular aspect, the pharmaceuticalcomposition is for use in the treatment of cystic fibrosis.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds of Formula (I)

wherein R¹, R², R^(2A), R³, R^(3A), R⁴, and R⁵ are defined above in theSummary and below in the Detailed Description. Further, compositionscomprising such compounds and methods for treating conditions anddisorders using such compounds and compositions are also included.

Compounds included herein may contain one or more variable(s) that occurmore than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds which can be isolated from a reactionmixture.

Definitions

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds; reference to “a pharmaceutically acceptablecarrier” means a single pharmaceutically acceptable carrier as well asone or more pharmaceutically acceptable carriers, and the like.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C₂-C₆ alkenyl” means analkenyl group containing 2-6 carbon atoms. Non-limiting examples ofC₂-C₆ alkenyl include buta-1,3-dienyl, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term “C₁-C₆ alkoxy” as used herein, means a C₁-C₆ alkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Non-limiting examples of alkoxy include methoxy, ethoxy,propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “C₁-C₆ alkoxy-C₁-C₆ alkyl” as used herein, means a C₁-C₆ alkoxygroup, as defined herein, appended to the parent molecular moietythrough a C₁-C₆ alkyl group, as defined herein. Representative examplesof C₁-C₆ alkoxy-C₁-C₆ alkyl include, but are not limited to,tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain radical. In some instances, the number of carbon atomsin an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein xis the minimum and y is the maximum number of carbon atoms in thesubstituent. Thus, for example, “C₁-C₆ alkyl” means an alkyl substituentcontaining from 1 to 6 carbon atoms and “C₁-C₃ alkyl” means an alkylsubstituent containing from 1 to 3 carbon atoms. Representative examplesof alkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl,1-ethylpropyl, and 1,2,2-trimethylpropyl. The terms “alkyl,” “C₁-C₆alkyl,” “C₁-C₄ alkyl,” and “C₁-C₃ alkyl” used herein are unsubstituted,unless otherwise indicated.

The term “alkylene” or “alkylenyl” means a divalent radical derived froma straight or branched, saturated hydrocarbon chain, for example, of 1to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1to 4 carbon atoms or of 1 to 3 carbon atoms (C₁-C₃ alkylenyl) or of 2 to6 carbon atoms (C₂-C₆ alkylenyl). Examples of C₁-C₆ alkylenyl include,but are not limited to, —CH₂—, —CH₂CH₂—, —C(CH₃)₂—CH₂CH₂CH₂—,—C(CH₃)₂—CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term, “alkenylene” as used herein, means a divalent radical derivedfrom a straight or branched hydrocarbon chain and containing at leastone carbon-carbon double bond. The term, “C₂-C₆ alkenylene” as usedherein, means a divalent radical derived from a straight or branchedhydrocarbon chain containing from 2 to 6 carbons and containing at leastone carbon-carbon double bond.

The term, “alkynylene” as used herein, means a divalent radical derivedfrom straight or branched chain hydrocarbon radical and containing atleast one carbon-carbon triple bond. The term, “C₂-C₆ alkynylene” asused herein, means a divalent radical derived from straight or branchedchain hydrocarbon radical containing from 2 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond.

The term “C₂-C₆ alkynyl” as used herein, means a straight or branchedchain hydrocarbon radical containing from 2 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of C₂-C₆ alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “C₃-C₁₁ cycloalkyl” as used herein, means a hydrocarbon ringradical containing 3-11 carbon atoms, zero heteroatoms, and zero doublebonds. The C₃-C₁₁ cycloalkyl group may be a single-ring (monocyclic) orhave two or more rings (polycyclic or bicyclic). Monocyclic cycloalkylgroups typically contain from 3 to 8 carbon ring atoms (C₃-C₈ monocycliccycloalkyl), and even more typically 3-6 carbon ring atoms (C₃-C₆monocyclic cycloalkyl). Examples of monocyclic cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyl groups contain two or more rings, andbicyclic cycloalkyls contain two rings. In certain embodiments, thepolycyclic cycloalkyl groups contain 2 or 3 rings. The rings within thepolycyclic and the bicyclic cycloalkyl groups may be in a bridged,fused, or spiro orientation, or combinations thereof. In a spirocycliccycloalkyl, one atom is common to two different rings. Examples of aspirocyclic cycloalkyl include spiro[2.5]octanyl and spiro[4.5]decanyl.In a bridged cycloalkyl, the rings share at least two non-adjacentatoms. Examples of bridged cycloalkyls include, but are not limited tobicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.2]nonyl,bicyclo[3.3.1]nonyl, and bicyclo[4.2.1]nonyl,tricyclo[3.3.1.0^(3,7)]nonyl (octahydro-2,5-methanopentalenyl ornoradamantyl), tricyclo[3.3.1.1^(3,7)]decyl (adamantyl), andtricyclo[4.3.1.1^(3,8)]undecyl (homoadamantyl). In a fused ringcycloalkyl, the rings share one common bond. Examples of fused-ringcycloalkyl include, but not limited to, decalin (decahydronaphthyl),bicyclo[3.1.0]hexanyl, and bicyclo[2.2.0]octyl.

The term “C₃-C₆ cycloalkyl” as used herein, means a hydrocarbon ringradical containing 3-6 carbon atoms, zero heteroatoms, and zero doublebonds. The C₃-C₆ cycloalkyl group may be a single-ring (monocyclic) orhave two rings (bicyclic).

The term “C₄-C₁₁ cycloalkenyl” as used herein, means a non-aromatichydrocarbon ring radical containing 4-11 carbon atoms, zero heteroatoms,and one or more double bonds. The C₄-C₁₁ cycloalkenyl group may be asingle-ring (monocyclic) or have two or more rings (polycyclic orbicyclic). Examples of monocyclic cycloalkenyl include cyclobutenyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctenyl,and cyclooctadienyl. Examples of bicyclic cycloalkenyl includebicyclo[2.2.1]hept-2-enyl.

The term “C₄-C₈ monocyclic cycloalkenyl” as used herein, meanscyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,cycloheptadienyl, cyclooctenyl, and cyclooctadienyl.

The term “C₄-C₇ monocyclic cycloalkenyl” as used herein, meanscyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, andcycloheptyl.

The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkylgroup, as defined herein, in which one, two, three, four, five, or sixhydrogen atoms are replaced by halogen. The term “C₁-C₃ haloalkyl” meansa C₁-C₃ alkyl group, as defined herein, in which one, two, three, four,or five hydrogen atoms are replaced by halogen. Representative examplesof haloalkyl include, but are not limited to, chloromethyl,2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl.

The term “haloalkoxy” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₆ haloalkoxy” means a C₁-C₆ alkoxygroup, as defined herein, in which one, two, three, four, five, or sixhydrogen atoms are replaced by halogen.

The term “4-12 membered heterocycle” as used herein, means a hydrocarbonring radical of 4-12 carbon ring atoms wherein at least one carbon atomis replaced by a heteroatom(s) independently selected from the groupconsisting of O, N, and S. The 4-12 membered heterocycle ring may be asingle ring (monocyclic) or have two or more rings (bicyclic orpolycyclic). In certain embodiments, the monocyclic heterocycle is afour-, five-, six-, seven-, or eight-membered hydrocarbon ring whereinat least one carbon ring atom is replaced by a heteroatom(s)independently selected from the group consisting of O, N, and S. Incertain embodiments, the monocyclic heterocycle is a 4-7 memberedhydrocarbon ring wherein at least one carbon ring atom is replaced by aheteroatom(s). A four-membered monocyclic heterocycle contains zero orone double bond, and one heteroatom selected from the group consistingof O, N, and S. A five-membered monocyclic heterocycle contains zero orone double bond and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. Examples of five-membered monocyclicheterocycles include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Non limitingexamples of 5-membered monocyclic heterocyclic groups include1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl,imidazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl,pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, andthiazolidinyl. A six-membered monocyclic heterocycle contains zero, one,or two double bonds and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. Examples of six-membered monocyclicheterocycles include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of six-memberedmonocyclic heterocycles include dihydropyranyl, 1,4-dioxanyl,1,3-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl,1,4-dihydropyridinyl, piperazinyl, piperidinyl, tetrahydropyranyl,1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl,thioxanyl, and trithianyl. Seven- and eight-membered monocyclicheterocycles contains zero, one, two, or three double bonds and one,two, or three heteroatoms selected from the group consisting of O, N,and S. Examples of monocyclic heterocycles include, but are not limitedto, azetidinyl, azepanyl, aziridinyl, 1,4-diazepanyl, dihydropyranyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxazepanyl, oxadiazolinyl,oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. Polycyclicheterocycle groups contain two or more rings, and bicyclic heterocyclescontain two rings. In certain embodiments, the polycyclic heterocyclegroups contain 2 or 3 rings. The rings within the polycyclic and thebicyclic heterocycle groups may be in a bridged, fused, or spiroorientation, or combinations thereof. In a spirocyclic heterocycle, oneatom is common to two different rings. Non limiting examples of thespirocyclic heterocycle include 6-oxaspiro[2.5]octanyl,2-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl,2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl,5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl,2-oxa-6-azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl,6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl,1-oxa-7-azaspiro[4.4]nonyl, 1-oxa-7-azaspiro[3.5]nonyl,1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl,1-oxa-4,9-diazaspiro[5.5]undecyl, 2-oxa-7-azaspiro[3.5]nonyl,5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.5]nonyl,7-oxa-2-azaspiro[3.5]nonyl, 8-oxa-2-azaspiro[4.5]decyl,2,7-diazaspiro[4.4]nonyl, 1,4-dioxa-8-azaspiro[4.5]decyl,1,3,8-triazaspiro[4.5]decyl. In a fused ring heterocycle, the ringsshare one common bond. Examples of fused bicyclic heterocycles are a 4-6membered monocyclic heterocycle fused to a phenyl group, or a 4-6membered monocyclic heterocycle fused to a C₃-C₆ monocyclic cycloalkyl,or a 4-6 membered monocyclic heterocycle fused to a C₄-C₇ monocycliccycloalkenyl, or a 4-6 membered monocyclic heterocycle fused to a 4-7membered monocyclic heterocycle. Examples of fused bicyclic heterocyclesinclude, but are not limited to, 1,2-dihydrophthalazinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, chromanyl, chromenyl,isochromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, isoindolinyl,2,3-dihydrobenzo[b]thienyl, hexahydro-1H-cyclopenta[c]furanyl,3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexyl, benzopyranyl,benzothiopyranyl, indolinyl, decahydropyrrolo[3,4-b]azepinyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl,2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl,hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,hexahydrocyclopenta[c]pyrrol-3a(1H)-yl,hexahydro-1H-oxazolo[3,4-a]pyrazinyl,octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydroimidazo[1,5-a]pyrazinyl,octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl,and octahydropyrrolo[3,4-c]pyrrolyl. In a bridged heterocycle, the ringsshare at least two non-adjacent atoms. Examples of such bridgedheterocycles include, but are not limited to,8-oxabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene,8-oxa-3-azabicyclo[3.2.1]octyl,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The nitrogen and sulfurheteroatoms in the heterocycle rings may optionally be oxidized (e.g.1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl,1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally bequaternized. Non limiting examples of the polycyclic heterocycle include6,7-dihydro-[1,3]dioxolo[4,5-J]benzofuranyl.

The term “4-6 membered heterocycle” as used herein, means a hydrocarbonring radical of 4-6 carbon ring atoms wherein at least one carbon atomis replaced by a heteroatom(s) independently selected from the groupconsisting of O, N, and S. A four-membered monocyclic heterocyclecontains zero or one double bond, and one heteroatom selected from thegroup consisting of O, N, and S. A five-membered monocyclic heterocyclecontains zero or one double bond and one, two, or three heteroatomsselected from the group consisting of O, N, and S. Examples offive-membered monocyclic heterocycles include those containing in thering: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N;or 1 O and 2 N. Non limiting examples of 5-membered monocyclicheterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl,oxazolidinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl,thiazolinyl, and thiazolidinyl. A six-membered monocyclic heterocyclecontains zero, one, or two double bonds and one, two, or threeheteroatoms selected from the group consisting of O, N, and S. Examplesof six-membered monocyclic heterocycles include those containing in thering: 1 O; 2 O; 1 S; 2 S; 1N; 2 N; 3N; 1 S, 1 O, and 1N; 1 Sand 1 N; 1 Sand 2N; 1 Sand 1 O; 1 S and 2 O; 1 O and 1N; and 1 O and 2 N. Examplesof six-membered monocyclic heterocycles include dihydropyranyl,1,4-dioxanyl, 1,3-dioxanyl, 1,4-dithianyl, hexahydropyrimidine,morpholinyl, 1,4-dihydropyridinyl, piperazinyl, piperidinyl,tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl,thiomorpholinyl, thioxanyl, and trithianyl.

The term “5-11 membered heteroaryl” as used herein, means a monocyclicheteroaryl and a bicyclic heteroaryl. The “5-7 membered heteroaryl” is afive- or six-membered ring. The five-membered ring contains two doublebonds. The five membered ring may contain one heteroatom selected from Oor S; or one, two, three, or four nitrogen atoms and optionally oneoxygen or one sulfur atom. The six-membered ring contains three doublebonds and one, two, three or four nitrogen atoms. Examples of 5-6membered monocyclic heteroaryl include, but are not limited to, furanyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl,pyridazinonyl, pyridinonyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl,thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of amonocyclic heteroaryl fused to a phenyl, or a monocyclic heteroarylfused to a C₃-C₆ monocyclic cycloalkyl, or a monocyclic heteroaryl fusedto C₄-C₇ monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to amonocyclic heteroaryl, or a monocyclic heteroaryl fused to a 4-7membered monocyclic heterocycle. Representative examples of bicyclicheteroaryl groups include, but are not limited to,4H-furo[3,2-b]pyrrolyl, benzofuranyl, benzothienyl, benzoisoxazolyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl,2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The nitrogen atom in the heteroarylrings may optionally be oxidized and may optionally be alkylated.

The term “6-10 membered aryl”, as used herein, means a hydrocarbon ringradical containing 6-10 carbon atoms, zero heteroatoms, and one or morearomatic rings. The 6-10 membered aryl group may be a single-ring(monocyclic) or have two rings (bicyclic). The bicyclic aryl isnaphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenylfused to a monocyclic cycloalkenyl. Representative examples of 6-10membered aryl groups include, but are not limited to, phenyl, indenyl,tetrahydronaphthalenyl, dihydroindenyl (indanyl), naphthyl, and thelike.

The aryls, the cycloalkyls, the cycloalkenyls, the heterocycles, and theheteroaryls, including the exemplary rings, are optionally substitutedunless otherwise indicated; and are attached to the parent molecularmoiety through any substitutable atom contained within the ring system.

The term “heteroatom” as used herein, means a nitrogen, oxygen, andsulfur.

The term “oxo” as used herein, means a ═O group.

The term “radiolabel” means a compound of the invention in which atleast one of the atoms is a radioactive atom or a radioactive isotope,wherein the radioactive atom or isotope spontaneously emits gamma raysor energetic particles, for example alpha particles or beta particles,or positrons. Examples of such radioactive atoms include, but are notlimited to, ³H (tritium), ¹⁴C, ¹¹C, ¹⁵O, ¹⁸F, ³⁵S, ¹²³I, and ¹²⁵I.

A moiety is described as “substituted” when a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heterocycle moiety is a heterocyclemoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocycle. It should be recognized that ifthere are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms. Incertain embodiments, “treat,” “treating,” and “treatment” refer toameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treat”,“treating”, and “treatment” refer to modulating the disease or disorder,either physically (for example, stabilization of a discernible symptom),physiologically (for example, stabilization of a physical parameter), orboth. In a further embodiment, “treat”, “treating”, and “treatment”refer to slowing the progression of the disease or disorder.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring or developing a disease or disorder.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another therapeutic agent fortreatment in a particular subject or subject population. The“therapeutically effective amount” may vary depending on the compound,the disease and its severity, and the age, weight, health, etc., of thesubject to be treated. For example in a human or other mammal, atherapeutically effective amount may be determined experimentally in alaboratory or clinical setting, or may be the amount required by theguidelines of the United States Food and Drug Administration, orequivalent foreign agency, for the particular disease and subject beingtreated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and thelike. In one embodiment, the subject is a human. The terms “human,”“patient,” and “subject” are used interchangeably herein.

The term “one or more” refers to one to eight. In one embodiment itrefers to one to eight. In one embodiment it refers to one to seven. Inone embodiment it refers to one to six. In one embodiment it refers toone to five. In one embodiment it refers to one to four. In oneembodiment it refers to one or three. In another embodiment it refers toone to three. In a further embodiment it refers to one to two. In yetother embodiment it refers to two. In yet other further embodiment itrefers to one.

The term “bioisostere”, as used herein, means a moiety withsubstantially similar physical or chemical properties that impartsimilar biological properties to the compound having Formula (I).Examples of —C(O)OH bioisosteres include —P(O)(OH)₂, —P(O)(OH)(H),—P(O)(OH)(O—C₁-C₆ alkyl), —P(O)(CH₃)(OH), —B(OH)₂, —SO₃H, —CH(OH)CF₃,—C(O)NH(OH), —C(O)NH(CN), —C(O)NHSO₂R^(G3a), —SO₂NHC(O)R^(G3a),—C(O)NHSO₂NHR^(G3a), —C(O)NHSO₂N(R^(G3a))₂, —SO₂NH₂, —SO₂NHR^(G3a),—SO₂N(R^(G3a))₂, —C(O)NHS(O)(R^(G3a))═NC(O)R^(G3a),—C(O)NHS(O)(R^(G3a))═NR^(G3b),

wherein

R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆alkyl-O—C₁-C₆ alkyl, C₁-C₆ haloalkyl, or G^(A);

R^(G3b) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl or G^(A);

G^(A), at each occurrence, is independently cycloalkyl, cycloalkenyl,aryl, or heteroaryl, each of which is independently unsubstituted orsubstituted with 1, 2, or 3 independently selected R^(u) groups; wherein

R^(u), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo, —NO₂, —OR^(j),—OC(O)R^(k), —OC(O)N(R^(j))₂, —S(O)₂R^(j), —S(O)₂N(R^(j))₂, —C(O)R^(k),—C(O)OR^(j), —C(O)N(R^(j))₂, —N(R^(j))₂, —N(R^(j))C(O)R^(k),—N(R^(j))S(O)₂R^(k), —N(R^(j))C(O)O(R^(k)), or —N(R^(j))C(O)N(R^(j))₂;

R^(j), at each occurrence, is independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl or C₁-C₆ haloalkyl.

As used herein, “Class I mutation(s)” refers to mutations whichinterfere with protein synthesis. They result in the introduction of apremature signal of termination of translation (stop codon) in the mRNA.The truncated CFTR proteins are unstable and rapidly degraded, so, thenet effect is that there is no protein at the apical membrane. Inparticular, Class I mutation(s) refers to p.Gly542X (G542X), W1282X,c.489+1G>T (621+1G>T), or c.579+1G>T (711+1G>T) mutation. Moreparticularly, Class I mutation(s) refers to G542X; or W1282X mutations.

As used herein, “Class II mutation(s)” refers to mutations which affectprotein maturation. These lead to the production of a CFTR protein thatcannot be correctly folded and/or trafficked to its site of function onthe apical membrane. In particular, Class II mutation(s) refers toPhe508del (F508del), Ile507del, or Asn1303Lys (N1303K) mutations. Moreparticularly, Class II mutation(s) refers to F508del or N1303Kmutations.

As used herein, “Class III mutation(s)” refers to mutations which alterthe regulation of the CFTR channel. The mutated CFTR protein is properlytrafficked and localized to the plasma membrane but cannot be activated,or it cannot function as a chloride channel. In particular, Class IIImutation(s) refers to p.Gly551Asp (G551D), G551S, R553G, G1349D, S1251N,G178R, S549N mutations. More particularly, Class III mutation(s) refersto G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.

As used herein, “Class IV mutation(s)” refers to mutations which affectchloride conductance. The CFTR protein is correctly trafficked to thecell membrane but generates reduced chloride flow or a “gating defect”(most are missense mutations located within the membrane-spanningdomain). In particular, Class IV mutation(s) refers to p.Arg117His(R117H), R347P, or p.Arg334Trp (R334W) mutations.

As used herein, “Class V mutation(s)” refers to mutations which reducethe level of normally functioning CFTR at the apical membrane or resultin a “conductance defect” (for example partially aberrant splicingmutations or inefficient trafficking missense mutations). In particular,Class V mutation(s) refers to c.1210-12T[5] (5T allele), c.S3140-26A>G(3272-26A>G), c.3850-2477C>T (3849+10kbC>T) mutations.

As used herein, “Class VI mutation(s)” refers to mutations whichdecrease the stability of the CFTR which is present or which affect theregulation of other channels, resulting in inherent instability of theCFTR protein. In effect, although functional, the CFTR protein isunstable at the cell surface and it is rapidly removed and degraded bycell machinery. In particular, Class VI mutation(s) refers to RescuedF508del, 120del23, N287Y, 4326dellTC, or 4279insA mutations. Moreparticularly, Class VI mutation(s) refers to Rescued F508del mutations.

Compounds

Compounds of the invention have the general Formula (I) as describedabove.

Particular values of variable groups are as follows. Such values may beused where appropriate with any of the other values, definitions, claimsor embodiments defined hereinbefore or hereinafter.

Formula (I)

One embodiment pertains to compounds of Formula (I),

wherein

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof;    -   R^(2A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein the R³        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³        C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I; and    -   R^(3A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, and C₁-C₆ haloalkyl; or    -   R³ and R^(3A), together with the carbon to which they are        attached, form a C₃-C₆ cycloalkyl; wherein the C₃-C₆ cycloalkyl        formed from R³ and R^(3A) and the carbon to which they are        attached is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I;    -   R⁴ is selected from the group consisting of L¹-C₆-C₁₀ aryl,        L¹-5-11 membered heteroaryl, L¹-4-12 membered heterocyclyl,        L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl; wherein the R⁴        C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 membered        heterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH,        oxo, CN, NO₂, F, Cl, Br and I;    -   L¹ is absent, or is selected from the group consisting of C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆        alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene,        and C₂-C₆ alkynylene, alone or as part of a group, are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, OH, and oxo;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, 4-6 membered monocyclic        heterocycle fused to a phenyl group, C₃-C₁₁ cycloalkyl, and        C₄-C₁₁ cycloalkenyl; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11        membered heteroaryl, 4-6 membered monocyclic heterocycle fused        to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br        and I; wherein the R⁶ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸,        NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R²¹, OR²¹,        C(O)R²¹, OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH,        oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,        C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and        5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6        membered heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,        N(C₁-C₆ alkyl)₂, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹⁵ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo,        OH, CN, NO₂, F, Cl, Br and I;    -   R¹⁶ and R¹⁷, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁸, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl,        Br and I;    -   R¹⁹ and R²⁰, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I;    -   R²² and R²³, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy-        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; and    -   R²⁵ and R²⁶, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl.

In one embodiment of Formula (I),

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof;    -   R^(2A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein the R³        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³        C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I; and    -   R^(3A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, and C₁-C₆ haloalkyl; or    -   R³ and R^(3A), together with the carbon to which they are        attached, form a C₃-C₆ cycloalkyl; wherein the C₃-C₆ cycloalkyl        formed from R³ and R^(3A) and the carbon to which they are        attached is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I;    -   R⁴ is selected from the group consisting of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ aryl, (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl, (C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl,        (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl, and (C₁-C₆        alkylene)_(x)-C₄-C₁₁ cycloalkenyl; wherein the R⁴ C₆-C₁₀        membered aryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl, the        5-11 membered heteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl, the 4-12 membered heterocyclyl of (C₁-C₆        alkylene)_(x)-4-12 membered heterocyclyl, the C₃-C₁₁ cycloalkyl        of (C₁-C₆ alkylene)_(x)C₃-C₁₁ cycloalkyl, and the C₄-C₁₁        cycloalkenyl of (C₁-C₆ alkylene)_(x)-C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH,        oxo, CN, NO₂, F, Cl, Br and I;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁        cycloalkenyl; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br        and I; wherein the R⁶ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸,        NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R²¹, OR²¹,        C(O)R²¹, OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH,        oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,        C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and        5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6        membered heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹⁵ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo,        OH, CN, NO₂, F, Cl, Br and I;    -   R¹⁶ and R¹⁷, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁸, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl,        Br and I;    -   R¹⁹ and R²⁰, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I;    -   R²² and R²³, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy-        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl;    -   R²⁵ and R²⁶, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl; and    -   x is 0 or 1.

In one embodiment of Formula (I), R¹ is selected from the groupconsisting of SO₂R⁶, C(O)R⁶, C(O)OR⁶, and C(O)NR⁷R⁸. In anotherembodiment of Formula (I), R¹ is C(O)R⁶ or C(O)OR⁶. In anotherembodiment of Formula (I), R¹ is SO₂R⁶. In another embodiment of Formula(I), R¹ is C(O)R⁶. In another embodiment of Formula (I), R¹ is C(O)OR⁶.In another embodiment of Formula (I), R¹ is C(O)NR⁷R⁸.

In one embodiment of Formula (I), R² is C(O)OH or a bioisostere thereof.In another embodiment of Formula (I), R² is selected from the groupconsisting of —P(O)(OH)₂, —P(O)(OH)(H), —P(O)(OH)(O—C₁-C₆ alkyl),—P(O)(CH₃)(OH), —B(OH)₂, —SO₃H, —CH(OH)CF₃, —C(O)NH(OH), —C(O)NH(CN),—C(O)NHSO₂R^(G3a), —SO₂NHC(O)R^(G3a), —C(O)NHSO₂NHR^(G3a),—C(O)NHSO₂N(R^(G3a))₂, —SO₂NH₂, —SO₂NHR^(G3a), —SO₂N(R^(G3a))₂,—C(O)NHS(O)(R^(G3a))═NC(O)R^(G3a), —C(O)NHS(O)(R^(G3a))═NR^(G3b),

wherein

R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆alkyl-O—C₁-C₆ alkyl, C₁-C₆ haloalkyl, or G^(A);

R^(G3b) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl or G^(A);

G^(A), at each occurrence, is independently cycloalkyl, cycloalkenyl,aryl, or heteroaryl, each of which is independently unsubstituted orsubstituted with 1, 2, or 3 independently selected R^(u) groups; wherein

R^(u), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo, —NO₂, —OR^(j),—OC(O)R^(k), —OC(O)N(R^(j))₂, —S(O)₂R^(j), —S(O)₂N(R^(j))₂, —C(O)R^(k),—C(O)OR^(j), —C(O)N(R^(j))₂, —N(R^(j))₂, —N(R^(j))C(O)R^(k),—N(R^(j))S(O)₂R^(k), —N(R^(j))C(O)O(R^(k)), or —N(R^(j))C(O)N(R^(j))₂;

R^(j), at each occurrence, is independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl or C₁-C₆ haloalkyl. In another embodiment ofFormula (I), R² is —P(O)(OH)₂, —P(O)(OH)(H), —B(OH)₂, —SO₃H, —CH(OH)CF₃,—C(O)NH(OH), —C(O)NH(CN), —C(O)NHSO₂R^(G3a), —SO₂NHC(O)R^(G3a),—C(O)NHSO₂NHR^(G3a), —C(O)NHSO₂N(R^(G3a))₂, —SO₂NH₂, —SO₂NHR^(G3a),—SO₂N(R^(G3a))₂, —C(O)NHS(O)(R^(G3a))═NC(O)R^(G3a),—C(O)NHS(O)(R^(G3a))═NR^(G3b), or

wherein

R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆alkyl-O—C₁-C₆ alkyl, C₁-C₆ haloalkyl, or G^(A);

R^(G3b) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl or G^(A);

G^(A), at each occurrence, is independently cycloalkyl, cycloalkenyl,aryl, or heteroaryl, each of which is independently unsubstituted orsubstituted with 1, 2, or 3 independently selected R^(u) groups; wherein

R^(u), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo, —NO₂, —OR^(j),—OC(O)R^(k), —OC(O)N(R^(j))₂, —S(O)₂R^(j), —S(O)₂N(R^(j))₂, —C(O)R^(k),—C(O)OR^(j), —C(O)N(R^(j))₂, —N(R^(j))₂, —N(R^(j))C(O)R^(k),—N(R^(j))S(O)₂R^(k), —N(R^(j))C(O)O(R^(k)), or —N(R^(j))C(O)N(R^(j))₂;

R^(j), at each occurrence, is independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl or C₁-C₆ haloalkyl.

In another embodiment of Formula (I), R² is C(O)OH. In anotherembodiment of Formula (I), R² is —C(O)NHSO₂R^(G3a) or—C(O)NHSO₂N(R^(G3a))₂; R^(G3a), at each occurrence, is independentlyC₁-C₆ alkyl, C₁-C₆ alkyl-O—C₁-C₆ alkyl, or G^(A); and G^(A), at eachoccurrence, is independently cycloalkyl, which is independentlyunsubstituted or substituted with 1, 2, or 3 independently selectedR^(u) groups; wherein R^(u), at each occurrence, is independently C₁-C₆alkyl. In another embodiment of Formula (I), R² is —C(O)NHSO₂R^(G3a);R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆alkyl-O—C₁-C₆ alkyl, or G^(A); and G^(A), at each occurrence, isindependently cycloalkyl, which is independently unsubstituted orsubstituted with 1, 2, or 3 independently selected R^(u) groups; whereinR^(u), at each occurrence, is independently C₁-C₆ alkyl. In anotherembodiment of Formula (I), R² is —C(O)NHSO₂N(R^(G3a))₂; and R^(G3a) ateach occurrence, is independently C₁-C₆ alkyl.

In one embodiment of Formula (I), R^(2A) is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl. In another embodiment of Formula (I), R^(2A) is hydrogen orC₁-C₆ alkyl. In another embodiment of Formula (I), R^(2A) is hydrogen.In another embodiment of Formula (I), R^(2A) is C₁-C₆ alkyl. In anotherembodiment of Formula (I), R^(2A) is CH₃.

In one embodiment of Formula (I), R² is C(O)OH; and R^(2A) is hydrogen.

In one embodiment of Formula (I),

-   -   R² is —P(O)(OH)₂, —P(O)(OH)(H), —B(OH)₂, —SO₃H, —CH(OH)CF₃,        —C(O)NH(OH), —C(O)NH(CN), —C(O)NHSO₂R^(G3a), —SO₂NHC(O)R^(G3a),        —C(O)NHSO₂NHR^(G3a), —C(O)NHSO₂N(R^(G3a))₂, —SO₂NH₂,        —SO₂NHR^(G3a), —SO₂N(R^(G3a))₂,        —C(O)NHS(O)(R^(G3a))═NC(O)R^(G3a),        —C(O)NHS(O)(R^(G3a))═NR^(G3b), or

-   -   R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆        alkyl-O—C₁-C₆ alkyl, C₁-C₆ haloalkyl, or G^(A);    -   R^(G3b) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl or G^(A);    -   G^(A), at each occurrence, is independently cycloalkyl,        cycloalkenyl, aryl, or heteroaryl, each of which is        independently unsubstituted or substituted with 1, 2, or 3        independently selected R^(u) groups; wherein    -   R^(u), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo,        —NO₂, —OR^(j), —OC(O)R^(k), —OC(O)N(R^(j))₂, —S(O)₂R^(j),        —S(O)₂N(R^(j))₂, —C(O)R^(k), —C(O)OR^(j), —C(O)N(R^(j))₂,        —N(R^(j))₂, —N(R^(j))C(O)R^(k), —N(R^(j))S(O)₂R^(k),        —N(R^(j))C(O)O(R^(k)), or —N(R^(j))C(O)N(R^(j))₂;    -   R^(j), at each occurrence, is independently selected from the        group consisting of hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   R^(k), at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl or C₁-C₆ haloalkyl; and

R^(2A) is hydrogen. In one embodiment of Formula (I),

-   -   R² is —C(O)NHSO₂R^(G3a) or —C(O)NHSO₂N(R^(G3a))₂;    -   R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆        alkyl-O—C₁-C₆ alkyl, or G^(A);    -   G^(A), at each occurrence, is independently cycloalkyl, which is        independently unsubstituted or substituted with 1, 2, or 3        independently selected R^(u) groups;    -   R^(u), at each occurrence, is independently C₁-C₆ alkyl; and    -   R^(2A) is hydrogen.

In one embodiment of Formula (I), R³ is selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein the R³ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; whereinthe R³ C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl areoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(3A) isindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, and C₁-C₆ haloalkyl. In another embodiment of Formula (I), R³ isselected from the group consisting of C₁-C₆ alkyl and C₃-C₆ cycloalkyl;wherein the R³ C₁-C₆ alkyl is optionally substituted with one or moreC₁-C₆ alkoxy; wherein the R³ C₃-C₆ cycloalkyl is optionally substitutedwith one or more C₁-C₆ alkyl; and R^(3A) is independently hydrogen. Inanother embodiment of Formula (I), R³ is C₁-C₆ alkyl; wherein the R³C₁-C₆ alkyl is optionally substituted with one or more C₁-C₆ alkoxy; andR^(3A) is independently hydrogen. In another embodiment of Formula (I),R³ is C₃-C₆ cycloalkyl; wherein the R³ C₃-C₆ cycloalkyl is optionallysubstituted with one or more C₁-C₆ alkyl; and R^(3A) is hydrogen. In oneembodiment of Formula (I), R³ is CH₃, and R^(3A) is hydrogen. In oneembodiment of Formula (I), R³ is C₁-C₆ alkyl and R^(3A) is hydrogen. Inone embodiment of Formula (I), R³ is C(CH₃)₃, and R^(3A) is hydrogen. Inone embodiment of Formula (I), R³ is C(OCH₃)(CH₃)₂, and R^(3A) ishydrogen. In one embodiment of Formula (I), R³ is cyclopropyl whereinthe R³ cyclopropyl is optionally substituted with one CH₃; and R^(3A) ishydrogen.

In one embodiment of Formula (I), R³ and R^(3A), together with thecarbon to which they are attached, form C₃-C₆ cycloalkyl; wherein theC₃-C₆ cycloalkyl formed from R³ and R^(3A) and the carbon to which theyare attached is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (I), R³ and R^(3A), together with the carbon towhich they are attached, form C₃-C₆ cycloalkyl, which is unsubstituted.In another embodiment of Formula (I), R³ and R^(3A), together with thecarbon to which they are attached, form cyclopropyl.

In one embodiment of Formula (I), R⁴ is selected from the groupconsisting of L¹-C₆-C₁₀ aryl, L¹-5-11 membered heteroaryl, L¹-4-12membered heterocyclyl, L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl;wherein the R⁴ C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 memberedheterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹,Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein L¹ isabsent, or is selected from the group consisting of C₁-C₆ alkylene,C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein theL¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or aspart of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo. In another embodiment of Formula (I), R⁴ isselected from the group consisting of L¹-C₆-C₁₀ aryl, and L¹-5-11membered heteroaryl; wherein the R⁴ C₆-C₁₀ aryl and 5-11 memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹,OH, Cl, and Br; wherein L¹ is absent, or is selected from the groupconsisting of C₁-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, andC₁-C₆ alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, andC₂-C₆ alkynylene, alone or as part of a group, are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆ alkoxy, OH, and oxo. In another embodimentof Formula (I), R⁴ is L¹-C₆-C₁₀ aryl; wherein the R⁴ C₆-C₁₀ aryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;wherein L¹ is absent, or is selected from the group consisting of C₁-C₆alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—;wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene,alone or as part of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo.

In another embodiment of Formula (I), R⁴ is L¹-5-11 membered heteroaryl;wherein the R⁴ 5-11 membered heteroaryl is optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; wherein L¹ is absent, oris selected from the group consisting of C₁-C₆ alkylene, C₂-C₆alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein the L¹C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or as partof a group, are optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkoxy, OH,and oxo.

In one embodiment of Formula (I), R⁴ is selected from the groupconsisting of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ aryl, (C₁-C₆alkylene)_(x)-5-11 membered heteroaryl, (C₁-C₆ alkylene)_(x)-4-12membered heterocyclyl, (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl, and(C₁-C₆ alkylene)_(x)-C₄-C₁₁ cycloalkenyl; wherein the R⁴ C₆-C₁₀ memberedaryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl, the 5-11 memberedheteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl, the 4-12membered heterocyclyl of (C₁-C₆ alkylene)_(x)-4-12 memberedheterocyclyl, the C₃-C₁₁ cycloalkyl of (C₁-C₆ alkylene)_(x)-C₃-C₁₁cycloalkyl, and the C₄-C₁₁ cycloalkenyl of (C₁-C₆ alkylene)_(x)-C₄-C₁₁cycloalkenyl are optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, C(O)OR⁹,C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl,Br and I; and x is 0 or 1. In another embodiment of Formula (I), R⁴ isselected from the group consisting of (C₁-C₆ alkylene)_(x)-C₆-C₁₀- aryl,(C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl, (C₁-C₆ alkylene)_(x)-4-12membered heterocyclyl, and (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl;wherein the R⁴ C₆-C₁₀ membered aryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀membered aryl, the 5-11 membered heteroaryl of (C₁-C₆ alkylene)_(x)-5-11membered heteroaryl, the 4-12 membered heterocyclyl of (C₁-C₆alkylene)_(x)-4-12 membered heterocyclyl, and the C₃-C₁₁ cycloalkyl of(C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl are optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0 or 1. Inanother embodiment of Formula (I), R⁴ is (C₁-C₆ alkylene)_(x)-C₆-C₁₀aryl; wherein the R⁴ (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;and x is 0 or 1.

In another embodiment of Formula (I), R⁴ is (C₁-C₆ alkylene)_(x)-5-11membered heteroaryl; wherein the R⁴ (C₁-C₆ alkylene)_(x)-5-11 memberedheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹,OH, Cl, and Br; and x is 0 or 1. In another embodiment of Formula (I),R⁴ is (C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl; wherein the R⁴(C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0or 1. In another embodiment of Formula (I), R⁴ is (C₁-C₆alkylene)_(x)-C₃-C₁₁ cycloalkyl; wherein the R⁴ (C₁-C₆ alkylene)C₃-3-C₁₁cycloalkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹,OH, Cl, and Br; and x is 0 or 1.

In one embodiment of Formula (I), R⁵ is selected from the groupconsisting of C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, 4-6membered monocyclic heterocycle fused to a phenyl group,C₃-C₁₁cycloalkyl, and C₄-C₁₁ cycloalkenyl; wherein the R⁵ C₆-C₁₀membered aryl, 5-11 membered heteroaryl, 4-6 membered monocyclicheterocycle fused to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁cycloalkenyl are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,OH, oxo, CN, NO₂, F, Cl, Br and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂,OH, oxo, CN, NO₂, F, Cl, Br and I; and R¹³ and R¹⁴, at each occurrence,are each independently hydrogen or C₁-C₆ alkyl. In another embodiment ofFormula (I), R⁵ is selected from the group consisting of C₆-C₁₀ memberedaryl, 5-11 membered heteroaryl, and 4-6 membered monocyclic heterocyclefused to a phenyl group; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11membered heteroaryl, and 4-6 membered monocyclic heterocycle fused to aphenyl group are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,F, Cl, Br, and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 memberedheterocyclyl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F,and Cl; and R¹³ and R¹⁴, at each occurrence, are each independentlyC₁-C₆ alkyl. In another embodiment of Formula (I), R⁵ is selected fromthe group consisting of C₆-C₁₀ membered aryl and 5-11 memberedheteroaryl; wherein the R⁵ C₆-C₁₀ membered aryl and 5-11 memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,F, Cl, Br, and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more independently selected C₁-C₆alkyl; and R¹³ and R¹⁴, at each occurrence, are each independently C₁-C₆alkyl.

In another embodiment of Formula (I), R⁵ is C₆-C₁₀ membered aryl;wherein the R⁵ C₆-C₁₀ membered aryl is optionally substituted with oneor more substituents independently selected from the group consisting ofR¹², OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F, and Cl; and R¹³ and R¹⁴, ateach occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (I), R⁵ is 5-11 membered heteroaryl; wherein theR⁵ 5-11 membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F, and Cl; and R¹³ and R¹⁴,at each occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (I), R⁵ is 5-11 membered heteroaryl; wherein theR⁵ 5-11 membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂,oxo, CN, F, and Cl; and R¹³ and R¹⁴, at each occurrence, are eachindependently C₁-C₆ alkyl. In another embodiment of Formula (I), R⁵ is5-11 membered heteroaryl; wherein the R⁵ 5-11 membered heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, and Br;R¹², at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;wherein each R¹² 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more independently selected C₁-C₆ alkyl; and R¹³and R¹⁴, at each occurrence, are each independently C₁-C₆ alkyl. Inanother embodiment of Formula (I), R⁵ is phenyl, which is unsubstituted.In another embodiment of Formula (I), R⁵ is phenyl; wherein the R⁵phenyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,F, Cl, and Br; R¹², at each occurrence, is independently selected fromthe group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; and R¹³ and R¹⁴, at each occurrence, are eachindependently C₁-C₆ alkyl. In another embodiment of Formula (I), R⁵ isphenyl; which is substituted with one R¹²; and R¹² is C₁-C₆ alkyl,C₃-C₁₁ cycloalkyl, or F. In another embodiment of Formula (I), R⁵ isphenyl; which is substituted with one R¹²; and R¹² is CH₃, CH₂CH₃ orCH(CH₃)₂. In another embodiment of Formula (I), R⁵ is phenyl; which issubstituted with one R¹²; and R¹² is cyclopropyl. In another embodimentof Formula (I), R⁵ is pyridinyl; which is substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², and NR¹³R¹⁴; R¹² is independently C₁-C₆ alkyl; and R¹³ and R¹⁴, ateach occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (I), R⁵ is pyridinyl; which is substituted withone or more substituents independently selected from the groupconsisting of R¹², OR¹², and NR¹³R¹⁴; R¹² is independently CH₃ orCH(CH₃)₂; and R¹³ and R¹⁴, at each occurrence, are each independentlyCH₃. In another embodiment of Formula (I), R⁵ is pyridinyl; wherein theR⁵ pyridinyl is optionally substituted with one or more independentlyselected R¹²; and R¹², at each occurrence, is independently C₁-C₆ alkyl.

In one embodiment of Formula (I), R⁶ is selected from the groupconsisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl,and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or moresubstituents independently selected from the group consisting of R¹⁵,OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br and I; wherein the R⁶ 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl are optionally substitutedwith one or more substituents independently selected from the groupconsisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸, NR¹⁹R²⁰,OH, oxo, CN, NO₂, F, Cl, Br and I; R¹⁵ at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I; R¹⁶ and R¹⁷, at eachoccurrence, are each independently hydrogen or C₁-C₆ alkyl; and R¹⁸, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (I), R⁶ is selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; whereinthe R⁶ C₁-C₆ alkyl is optionally substituted with one or moreindependently selected R¹⁵ or F; wherein the R⁶ 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclylare optionally substituted with one or more substituents independentlyselected from the group consisting of R¹⁸ and OR¹⁸; R¹⁵, at eachoccurrence, is independently C₃-C₁₁ cycloalkyl; and R¹⁸, at eachoccurrence, is independently selected C₁-C₆ alkyl; wherein each R¹⁸C₁-C₆ alkyl is optionally substituted with one or more F. In oneembodiment of Formula (I), R⁶ is C₁-C₆ alkyl; wherein the R⁶ C₁-C₆ alkylis optionally substituted with one or more independently selected R¹⁵;and R¹⁵, at each occurrence, is independently C₃-C₁₁ cycloalkyl. Inanother embodiment of Formula (I), R⁶ is C₁-C₆ alkyl; wherein the R⁶C₁-C₆ alkyl is unsubstituted. In another embodiment of Formula (I), R⁶is —CH₂CH₃. In another embodiment of Formula (I), R⁶ is —CH(CH₃)₂. Inone embodiment of Formula (I), R⁶ is 4-12 membered heterocyclyl; whereinthe R⁶ 4-12 membered heterocyclyl is optionally substituted with one ormore substituents independently selected from the group consisting ofOR¹⁸; and R¹⁸, at each occurrence, is independently C₁-C₆ alkyl. Inanother embodiment of Formula (I), R⁶ is 4-12 membered heterocyclyl;wherein the R⁶ 4-12 membered heterocyclyl is unsubstituted. In anotherembodiment of Formula (I), R⁶ is tetrahydrofuranyl. In anotherembodiment of Formula (I), R⁶ is tetrahydropyranyl. In one embodiment ofFormula (I), R⁶ is C₃-C₁₁ cycloalkyl; wherein the R⁶ C₃-C₁₁ cycloalkylis optionally substituted with one or more independently selected OR¹⁸;and R¹⁸, at each occurrence, is independently selected C₁-C₆ alkyl. Inone embodiment of Formula (I), R⁶ is cyclohexyl; wherein the R⁶cyclohexyl is unsubstituted.

In one embodiment of Formula (I), R¹ is C(O)OR⁶; and R⁶ is C₁-C₆ alkylor C₃-C₁₁ cycloalkyl. In one embodiment of Formula (I), R¹ is C(O)OR⁶;and R⁶ is C₁-C₆ alkyl; wherein the R⁶ is C₁-C₆ unsubstituted alkyl.

In one embodiment of Formula (I), R¹ is C(O)R⁶; R⁶ is 4-12 memberedheterocyclyl; wherein the R⁶ 4-12 membered heterocyclyl is optionallysubstituted with OR¹⁸; and R¹⁸, at each occurrence, is independentlyselected C₁-C₆ alkyl. In one embodiment of Formula (I), R¹ is C(O)R⁶;and R⁶ is 4-12 membered heterocyclyl; wherein the R⁶ 4-12 memberedheterocyclyl is unsubstituted. In one embodiment of Formula (I), R¹ isC(O)R⁶; and R⁶ is C₃-C₁₁ cycloalkyl; wherein the R⁶ C₃-C₁₁ cycloalkyl isunsubstituted.

In one embodiment of Formula (I), R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R²¹, OR²¹, C(O)R²¹, OC(O)R²¹,C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH, oxo, CN, NO₂, F, Cl, Br andI; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I; R²¹, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;R²² and R²³, at each occurrence, are each independently hydrogen orC₁-C₆ alkyl; R²⁴, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy- C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; and R²⁵ and R²⁶, at each occurrence, are eachindependently hydrogen or C₁-C₆ alkyl. In another embodiment of Formula(I), R⁹, at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁ cycloalkyl, and4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more CN or F; wherein each R⁹ 6-10 memberedaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R²⁴, OR²⁴, and F; and R²⁴, at each occurrence,is independently C₁-C₆ alkyl.

In one embodiment of Formula (I), R¹⁰ and R¹¹, at each occurrence, areeach independently selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl, and 5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹phenyl and 5-6 membered heteroaryl is optionally substituted with one ormore substituents independently selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br,and I. In another embodiment of Formula (I), R¹⁰ and R¹¹, at eachoccurrence, are each independently C₁-C₆ alkyl.

In one embodiment of Formula (I), R⁴ is L¹-C₆-C₁₀ aryl; wherein the R⁴C₆-C₁₀ aryl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹ and OR⁹; L¹ isabsent, or is C₁-C₆ alkylene; and R⁹, at each occurrence, isindependently selected C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl isoptionally substituted with one or more F. In one embodiment of Formula(I), R⁴ is (C₁-C₆ alkylene)_(x)-C₆-C₁₀ aryl; wherein the R⁴ (C₁-C₆alkylene)_(x)-C₆-C₁₀ membered aryl is optionally substituted with one ormore substituents independently selected from the group consisting of R⁹and OR⁹; x is 0 or 1; and R⁹, at each occurrence, is independentlyselected C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more F. In another embodiment of Formula (I), R⁴is CH₂-phenyl; wherein the R⁴ CH₂-phenyl is optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹ and OR⁹; and R⁹, at each occurrence, is independentlyselected from the group consisting of CH₃ and CF₃. In another embodimentof Formula (I), R⁴ is L¹-5-11 membered heteroaryl; wherein the R⁴ 5-11membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹ andOR⁹; L¹ is absent, or is C₁-C₆ alkylene; and R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl andC₃-C₁₁ cycloalkyl; wherein each R⁹ C₁-C₆ alkyl is optionally substitutedwith one or more F. In another embodiment of Formula (I), R⁴ is (C₁-C₆alkylene)_(x)-5-11 membered heteroaryl; wherein the R⁴ (C₁-C₆alkylene)_(x)-5-11 membered heteroaryl is optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹ and OR⁹; x is 0 or 1; and R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl andC₃-C₁₁cycloalkyl; wherein each R⁹ C₁-C₆ alkyl is optionally substitutedwith one or more F. In another embodiment of Formula (I), R⁴ isCH₂-pyridinyl; wherein the R⁴ CH₂— pyridinyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹ and OR⁹; and R⁹, at each occurrence, is independentlyselected from the group consisting of CH₃, C(CH₃)₃, CF₃, and cyclobutyl.In another embodiment of Formula (I), R⁴ is CH₂-quinolinyl; wherein theR⁴ CH₂— quinolinyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹ andOR⁹; and R⁹, at each occurrence, is independently CH₃.

In one embodiment of Formula (I), R⁴ is selected from the groupconsisting of

wherein R^(x) is OCH₃, and R^(y) is selected from the group consistingof CF₃, C(CH₃)₃, and cyclobutyl; and n is 1.

One embodiment pertains to compounds of Formula (I),

wherein

-   -   R¹ is C(O)R⁶;    -   R⁴ is L¹-5-11 membered heteroaryl; wherein the R⁴ 5-11 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        R⁹ and OR⁹;    -   L¹ is C₁-C₆ alkylene;    -   R⁵ is C₆-C₁₀ membered aryl; wherein the R⁵ C₆-C₁₀ membered aryl        is optionally substituted with one or more R¹²;    -   R⁶ is 4-12 membered heterocyclyl;    -   R⁹, at each occurrence, is independently selected C₁-C₆ alkyl;        wherein each R⁹ C₁-C₆ alkyl is optionally substituted with one        or more F; and    -   R¹², at each occurrence, is independently selected C₁-C₆ alkyl.

One embodiment pertains to compounds of Formula (I),

wherein

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof,    -   R^(2A) is hydrogen;    -   R³ is C₁-C₆ alkyl; wherein the R³ C₁-C₆ alkyl is optionally        substituted with one or more C₁-C₆ alkoxy;    -   R^(3A) is hydrogen;    -   R⁴ is selected from the group consisting of L¹-C₆-C₁₀ aryl and        L¹-5-11 membered heteroaryl; wherein the R⁴ C₆-C₁₀ aryl and 5-11        membered heteroaryl are optionally substituted with one or more        substituents independently selected from the group consisting of        R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;    -   L¹ is absent, or is selected from the group consisting of C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆        alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene,        and C₂-C₆ alkynylene, alone or as part of a group, are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, OH, and oxo;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, and 4-6 membered monocyclic        heterocycle fused to a phenyl group; wherein the R⁵ C₆-C₁₀        membered aryl, 5-11 membered heteroaryl, and 4-6 membered        monocyclic heterocycle fused to a phenyl group are optionally        substituted with one or more substituents independently selected        from the group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, Br and        I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆        alkyl is optionally substituted with one or more substituents        independently selected from the group consisting of R⁵ and F;        wherein the R⁶ 5-11 membered heteroaryl, and C₃-C₁₁ cycloalkyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R¹⁸ and        OR¹⁸;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        CN, and F; wherein each R⁹ 6-10 membered aryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, and F;    -   R¹⁰ and R¹¹, at each occurrence, are each independently C₁-C₆        alkyl;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12        membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11        membered heteroaryl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆        alkyl)₂, oxo, CN, F, and Cl;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently C₃-C₁₁ cycloalkyl;    -   R¹⁸, at each occurrence, is independently C₁-C₆ alkyl; wherein        each R¹⁸ C₁-C₆ alkyl is optionally substituted with one or more        F; and    -   R²⁴, at each occurrence, is C₁-C₆ alkyl.

In one embodiment of Formula (I),

-   -   R¹ is selected from the group consisting of C(O)R⁶, C(O)OR⁶, and        C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof,    -   R^(2A) is hydrogen;    -   R³ is C₁-C₆ alkyl;    -   R^(3A) is hydrogen;    -   R⁴ is selected from the group consisting of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ aryl and (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl; wherein the R⁴ C₆-C₁₀ membered aryl of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ membered aryl, and the 5-11 membered        heteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        NR¹⁰R¹¹, OH, Cl, and Br;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered aryl        and 5-11 membered heteroaryl; wherein the R⁵ C₆-C₁₀ membered        aryl and 5-11 membered heteroaryl are optionally substituted        with one or more substituents independently selected from the        group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, and Br;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;        wherein the R⁶ C₁-C₆ alkyl is optionally substituted with one or        more independently selected R¹⁵; wherein the R⁶ 6C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl are optionally        substituted with one or more independently selected OR¹⁸;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹        C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally        substituted with one or more F; wherein each R⁹ 6-10 membered        C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, and F;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        C₁-C₆ alkyl;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12        membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered        heterocyclyl is optionally substituted with one or more        independently selected from the group consisting of C₁-C₆ alkyl;    -   R¹³ and R¹⁴, at each occurrence, are each independently C₁-C₆        alkyl;    -   R¹⁵, at each occurrence, is independently selected C₃-C₁₁        cycloalkyl;    -   R¹⁸, at each occurrence, is independently selected C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected C₁-C₆ alkyl;        and    -   x is 0 or 1.

Exemplary compounds of Formula (I) include, but are not limited to

-   rac-(2R,3S,5R)-3-tert-butyl-1-(cyclopentylacetyl)-4-[(2,5-dichlorophenyl)methoxy]-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2,5-dichlorophenyl)methoxy]-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]oxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-4-[(4,6-dimethoxypyrimidin-2-yl)oxy]-1-[di(propan-2-yl)carbamoyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2R*,3S*,4R*,5R*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S*,3R*,4S*,5S*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-5-yl)methoxy]-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-2-yl)methoxy]-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-4-[(4-chloro-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)pyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-[2-(dimethylamino)pyridin-3-yl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(methanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   rac-(2R,3S,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(2-methoxyethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-N-(1-methylcyclopropane-1-sulfonyl)-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(cyclopropanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(ethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(dimethylsulfamoyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(methanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2R,3S,4R,5R)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2R,3S,4R,5R)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]oxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,4R,5R)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,4R,5R)-3-tert-butyl-1-[(cyclobutyloxy)carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   rac-(2R,3S,4R,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-1-[(cyclobutyloxy)carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclohexyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluoro-4-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(4-fluoro-2-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2,4-difluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(4-methylphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(3-chiorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(piperidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoroazetidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoropyrrolidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(prop-2-en-1-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-cyclobutyl-5-methoxypyridin-4-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]phenyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(3,6-dihydro-2H-pyran-4-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-(oxane-4-carbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(oxane-4-carbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(oxane-4-carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-1-(ethoxycarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-3-tert-butyl-1-(cyclopentanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-[2-(difluoromethyl)phenyl]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4R,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2,6-difluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-([1,1′-biphenyl]-2-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-cyanopropan-2-yl)-2-methoxyphenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrazol-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[3′-(dimethylamino)    [1,1′-biphenyl]-2-yl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2′-methyl[1,1′-biphenyl]-2-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyridin-4-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyrimidin-5-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(furan-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrrol-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[3′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-[2-(2H-1,3-benzodioxol-5-yl)phenyl]-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(6-methoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[4′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-cyano[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-{2-[6-(trifluoromethyl)pyridin-3-yl]phenyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(5-ethoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(1-benzofuran-7-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(2-methylpropyl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(6-methoxypyridine-2-sulfonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopropyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-7-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethoxy)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)—N-(6-aminopyridine-2-sulfonyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-3-methoxypyridin-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({[2-methoxy-5-(trifluoromethyl)pyridin-3-yl](²H₂)methyl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)pyridin-3-yl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)phenyl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[(5-tert-butyl-2-methoxyphenyl)(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-chloro-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-6,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-8-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({2-[2-methoxy-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-1-(cyclohexanecarbonyl)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxoethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-{[(1,1,1-trifluoropropan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2R)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-hydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-methoxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-3-(2-methoxypropan-2-yl)-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopropane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopentane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-4-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]propoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-iodo-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1R,2R)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1S,2S)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[(5-chloro-2-methoxypyridin-3-yl)oxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(²H₃)methylphenyl]-1-[(2S,3S)-(2,3-²H₂)oxane-2-carbonyl](2-²H)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenoxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-1-benzofuran-2-yl)methoxy]-3-tert-butyl-1-[(2)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]-4-{[7-(trifluoromethyl)-1-benzofuran-2-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-1-benzofuran-2-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(naphthalene-1-sulfonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-1-benzofuran-2-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid; and pharmaceutically acceptable salts thereof.

One embodiment pertains to a compound, or a pharmaceutically acceptablesalt thereof, wherein the compound is selected from the group consistingof:

-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,    S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid; and-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid.

One embodiment pertains to(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.

One embodiment pertains to(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.

One embodiment pertains to(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.

One embodiment pertains to(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.

One embodiment pertains to a compound, or a pharmaceutically acceptablesalt thereof, wherein the compound is selected from the group consistingof:

-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid; and-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.

One embodiment pertains to(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.

One embodiment pertains to(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.

One embodiment pertains to(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.

Formula (II)

One embodiment pertains to compounds of Formula (II),

wherein

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof;    -   R^(2A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein the R³        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³        C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I; and    -   R^(3A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, and C₁-C₆ haloalkyl; or    -   R³ and R^(3A), together with the carbon to which they are        attached, form a C₃-C₆ cycloalkyl; wherein the C₃-C₆ cycloalkyl        formed from R³ and R^(3A) and the carbon to which they are        attached is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I;    -   R⁴ is selected from the group consisting of L¹-C₆-C₁₀ aryl,        L¹-5-11 membered heteroaryl, L¹-4-12 membered heterocyclyl,        L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl; wherein the R⁴        C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 membered        heterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH,        oxo, CN, NO₂, F, Cl, Br and I;    -   L¹ is absent, or is selected from the group consisting of C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆        alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene,        and C₂-C₆ alkynylene, alone or as part of a group, are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, OH, and oxo;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, 4-6 membered monocyclic        heterocycle fused to a phenyl group, C₃-C₁₁ cycloalkyl, and        C₄-C₁₁ cycloalkenyl; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11        membered heteroaryl, 4-6 membered monocyclic heterocycle fused        to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br        and I; wherein the R⁶ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸,        NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R²¹, OR²¹,        C(O)R²¹, OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH,        oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,        C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and        5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6        membered heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,        N(C₁-C₆ alkyl)₂, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R¹⁵C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹⁵ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo,        OH, CN, NO₂, F, Cl, Br and I;    -   R¹⁶ and R¹⁷, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁸, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl,        Br and I;    -   R¹⁹ and R²⁰, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I;    -   R²² and R²³, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy-        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; and    -   R²⁵ and R²⁶, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl.

In one embodiment of Formula (II),

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof;    -   R^(2A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein the R³        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³        C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I; and    -   R^(3A) is selected from the group consisting of hydrogen, C₁-C₆        alkyl, and C₁-C₆ haloalkyl; or    -   R³ and R^(3A), together with the carbon to which they are        attached, form a C₃-C₆ cycloalkyl; wherein the C₃-C₆ cycloalkyl        formed from R³ and R^(3A) and the carbon to which they are        attached is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and        I;    -   R⁴ is selected from the group consisting of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ aryl, (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl, (C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl,        (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl, and (C₁-C₆        alkylene)_(x)-C₄-C₁₁ cycloalkenyl; wherein the R⁴ C₆-C₁₀        membered aryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl, the        5-11 membered heteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl, the 4-12 membered heterocyclyl of (C₁-C₆        alkylene)_(x)-4-12 membered heterocyclyl, the C₃-C₁₁ cycloalkyl        of (C₁-C₆ alkylene)_(x)C₃-3-C₁₁ cycloalkyl, and the C₄-C₁₁        cycloalkenyl of (C₁-C₆ alkylene)_(x)-C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH,        oxo, CN, NO₂, F, Cl, Br and I;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁        cycloalkenyl; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br        and I; wherein the R⁶ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸,        NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R²¹, OR²¹,        C(O)R²¹, OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH,        oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,        C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and        5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6        membered heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹⁵ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo,        OH, CN, NO₂, F, Cl, Br and I;    -   R¹⁶ and R¹⁷, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁸, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl,        Br and I;    -   R¹⁹ and R²⁰, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I;    -   R²² and R²³, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy-        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl;    -   R²⁵ and R²⁶, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl; and    -   x is 0 or 1.

In one embodiment of Formula (II), R¹ is selected from the groupconsisting of SO₂R⁶, C(O)R⁶, C(O)OR⁶, and C(O)NR⁷R⁸. In anotherembodiment of Formula (II), R¹ is C(O)R⁶ or C(O)OR⁶. In anotherembodiment of Formula (II), R¹ is SO₂R⁶. In another embodiment ofFormula (II), R¹ is C(O)R⁶. In another embodiment of Formula (II), R¹ isC(O)OR⁶. In another embodiment of Formula (II), R¹ is C(O)NR⁷R⁸.

In one embodiment of Formula (II), R² is C(O)OH or a bioisosterethereof. In another embodiment of Formula (II), R² is selected from thegroup consisting of —P(O)(OH)₂, —P(O)(OH)(H), —P(O)(OH)(O—C₁-C₆ alkyl),—P(O)(CH₃)(OH), —B(OH)₂, —SO₃H, —CH(OH)CF₃, —C(O)NH(OH), —C(O)NH(CN),—C(O)NHSO₂R^(G3a), —SO₂NHC(O)R^(G3a), —C(O)NHSO₂NHR^(G3a),—C(O)NHSO₂N(R^(G3a))₂, —SO₂NH₂, —SO₂NHR^(G3a), —SO₂N(R^(G3a))₂,—C(O)NHS(O)(R^(G3a))═NC(O)R^(G3a), —C(O)NHS(O)(R^(G3a))═NR^(G3b),

wherein

R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆alkyl-O—C₁-C₆ alkyl, C₁-C₆ haloalkyl, or G^(A);

R^(G3b) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl or G^(A);

G^(A), at each occurrence, is independently cycloalkyl, cycloalkenyl,aryl, or heteroaryl, each of which is independently unsubstituted orsubstituted with 1, 2, or 3 independently selected R^(u) groups; wherein

R^(u), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo, —NO₂, —OR^(j),—OC(O)R^(k), —OC(O)N(R^(j))₂, —S(O)₂R^(j), —S(O)₂N(R^(j))₂, —C(O)R^(k),—C(O)OR^(j), —C(O)N(R^(j))₂, —N(R^(j))₂, —N(R^(j))C(O)R^(k),—N(R^(j))S(O)₂R^(k), —N(R^(j))C(O)O(R^(k)), or —N(R^(j))C(O)N(R^(j))₂;

R^(j), at each occurrence, is independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl or C₁-C₆ haloalkyl. In another embodiment ofFormula (II), R² is —P(O)(OH)₂, —P(O)(OH)(H), —B(OH)₂, —SO₃H,—CH(OH)CF₃, —C(O)NH(OH), —C(O)NH(CN), —C(O)NHSO₂R^(G3a),—SO₂NHC(O)R^(G3a), —C(O)NHSO₂NHR^(G3a), —C(O)NHSO₂N(R^(G3a))₂, —SO₂NH₂,—SO₂NHR^(G3a), —SO₂N(R^(G3a))₂, —C(O)NHS(O)(R^(G3a))═NC(O)R^(G3a),—C(O)NHS(O)(R^(G3a))═NR^(G3b), or

wherein

R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆alkyl-O—C₁-C₆ alkyl, C₁-C₆ haloalkyl, or G^(A);

R^(G3b) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl or G^(A);

G^(A), at each occurrence, is independently cycloalkyl, cycloalkenyl,aryl, or heteroaryl, each of which is independently unsubstituted orsubstituted with 1, 2, or 3 independently selected R^(u) groups; wherein

R^(u), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo, —NO₂, —OR^(j),—OC(O)R^(k), —OC(O)N(R^(j))₂, —S(O)₂R^(j), —S(O)₂N(R^(j))₂, —C(O)R^(k),—C(O)OR^(j), —C(O)N(R^(j))₂, —N(R^(j))₂, —N(R^(j))C(O)R^(k),—N(R^(j))S(O)₂R^(k), —N(R^(j))C(O)O(R^(k)), or —N(R^(j))C(O)N(R^(j))₂;

R^(j), at each occurrence, is independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl or C₁-C₆ haloalkyl. In another embodiment ofFormula (II), R² is C(O)OH. In another embodiment of Formula (II), R² is—C(O)NHSO₂R^(G3a) or —C(O)NHSO₂N(R^(G3a))₂; R^(G3a), at each occurrence,is independently C₁-C₆ alkyl, C₁-C₆ alkyl-O—C₁-C₆ alkyl, or G^(A); andG^(A), at each occurrence, is independently cycloalkyl, which isindependently unsubstituted or substituted with 1, 2, or 3 independentlyselected R^(u) groups; wherein R^(u), at each occurrence, isindependently C₁-C₆ alkyl. In another embodiment of Formula (II), R² is—C(O)NHSO₂R^(G3a); R^(G3a), at each occurrence, is independently C₁-C₆alkyl, C₁-C₆ alkyl-O—C₁-C₆ alkyl, or G^(A); and G^(A), at eachoccurrence, is independently cycloalkyl, which is independentlyunsubstituted or substituted with 1, 2, or 3 independently selectedR^(u) groups; wherein R^(u), at each occurrence, is independently C₁-C₆alkyl. In another embodiment of Formula (II), R² is—C(O)NHSO₂N(R^(G3a))₂; and R^(G3a), at each occurrence, is independentlyC₁-C₆ alkyl.

In one embodiment of Formula (II), R^(2A) is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl. In another embodiment of Formula (II), R^(2A) is hydrogen orC₁-C₆ alkyl. In another embodiment of Formula (II), R^(2A) is hydrogen.In another embodiment of Formula (II), R^(2A) is C₁-C₆ alkyl. In anotherembodiment of Formula (II), R^(2A) is CH₃.

In one embodiment of Formula (II), R² is C(O)OH; and R^(2A) is hydrogen.

In one embodiment of Formula (II),

-   -   R² is —P(O)(OH)₂, —P(O)(OH)(H), —B(OH)₂, —SO₃H, —CH(OH)CF₃,        —C(O)NH(OH), —C(O)NH(CN), —C(O)NHSO₂R^(G3a), —SO₂NHC(O)R^(G3a),        —C(O)NHSO₂NHR^(G3a), —C(O)NHSO₂N(R^(G3a))₂, —SO₂NH₂,        —SO₂NHR^(G3a), —SO₂N(R^(G3a))₂,        —C(O)NHS(O)(R^(G3a))═NC(O)R^(G3a),        —C(O)NHS(O)(R^(G3a))═NR^(G3b), or

-   -   R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆        alkyl-O—C₁-C₆ alkyl, C₁-C₆ haloalkyl, or G^(A);    -   R^(G3b) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl or G^(A);    -   G^(A), at each occurrence, is independently cycloalkyl,        cycloalkenyl, aryl, or heteroaryl, each of which is        independently unsubstituted or substituted with 1, 2, or 3        independently selected R^(u) groups; wherein    -   R^(u), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo,        —NO₂, —OR^(j), —OC(O)R^(k), —OC(O)N(R^(j))₂, —S(O)₂R^(j),        —S(O)₂N(R^(j))₂, —C(O)R^(k), —C(O)OR^(j), —C(O)N(R^(j))₂,        —N(R^(j))₂, —N(R^(j))C(O)R^(k), —N(R^(j))S(O)₂R^(k),        —N(R^(j))C(O)O(R^(k)), or —N(R^(j))C(O)N(R^(j))₂;    -   R^(j), at each occurrence, is independently selected from the        group consisting of hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   R^(k), at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl or C₁-C₆ haloalkyl; and    -   R^(2A) is hydrogen.

In one embodiment of Formula (II),

-   -   R² is —C(O)NHSO₂R^(G3a) or —C(O)NHSO₂N(R^(G3a))₂;    -   R^(G3a), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆        alkyl-O—C₁-C₆ alkyl, or G^(A);    -   G^(A), at each occurrence, is independently cycloalkyl, which is        independently unsubstituted or substituted with 1, 2, or 3        independently selected R^(u) groups;    -   R^(u), at each occurrence, is independently C₁-C₆ alkyl; and    -   R^(2A) is hydrogen.

In one embodiment of Formula (II), R³ is selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein the R³ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; whereinthe R³ C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl areoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(3A) isindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, and C₁-C₆ haloalkyl. In another embodiment of Formula (II), R³ isselected from the group consisting of C₁-C₆ alkyl and C₃-C₆ cycloalkyl;wherein the R³ C₁-C₆ alkyl is optionally substituted with one or moreC₁-C₆ alkoxy; wherein the R³ C₃-C₆ cycloalkyl is optionally substitutedwith one or more C₁-C₆ alkyl; and R^(3A) is independently hydrogen. Inanother embodiment of Formula (II), R³ is C₁-C₆ alkyl; wherein the R³C₁-C₆ alkyl is optionally substituted with one or more C₁-C₆ alkoxy; andR^(3A) is independently hydrogen. In another embodiment of Formula (II),R³ is C₃-C₆ cycloalkyl; wherein the R³ C₃-C₆ cycloalkyl is optionallysubstituted with one or more C₁-C₆ alkyl; and R^(3A) is hydrogen. In oneembodiment of Formula (II), R³ is CH₃, and R^(3A) is hydrogen. In oneembodiment of Formula (II), R³ is C₁-C₆ alkyl and R^(3A) is hydrogen. Inone embodiment of Formula (II), R³ is C(CH₃)₃, and R^(3A) is hydrogen.In one embodiment of Formula (II), R³ is C(OCH₃)(CH₃)₂, and R^(3A) ishydrogen. In one embodiment of Formula (II), R³ is cyclopropyl whereinthe R³ cyclopropyl is optionally substituted with one CH₃; and R^(3A) ishydrogen.

In one embodiment of Formula (II), R³ and R^(3A), together with thecarbon to which they are attached, form C₃-C₆ cycloalkyl; wherein theC₃-C₆ cycloalkyl formed from R³ and R^(3A) and the carbon to which theyare attached is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (II), R³ and R^(3A), together with the carbon towhich they are attached, form C₃-C₆ cycloalkyl, which is unsubstituted.In another embodiment of Formula (II), R³ and R^(3A), together with thecarbon to which they are attached, form cyclopropyl.

In one embodiment of Formula (II), R⁴ is selected from the groupconsisting of L¹-C₆-C₁₀ aryl, L¹-5-11 membered heteroaryl, L¹-4-12membered heterocyclyl, L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl;wherein the R⁴ C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 memberedheterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹,Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein L¹ isabsent, or is selected from the group consisting of C₁-C₆ alkylene,C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein theL¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or aspart of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo. In another embodiment of Formula (II), R⁴ isselected from the group consisting of L¹-C₆-C₁₀ aryl and L¹-5-11membered heteroaryl; wherein the R⁴ C₆-C₁₀ aryl and 5-11 memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹,OH, Cl, and Br; wherein L¹ is absent, or is selected from the groupconsisting of C₁-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, andC₁-C₆ alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, andC₂-C₆ alkynylene, alone or as part of a group, are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆ alkoxy, OH, and oxo. In another embodimentof Formula (II), R⁴ is L¹-C₆-C₁₀ aryl; wherein the R⁴ C₆-C₁₀ aryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;wherein L¹ is absent, or is selected from the group consisting of C₁-C₆alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—;wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene,alone or as part of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo.

In another embodiment of Formula (II), R⁴ is L¹-5-11 memberedheteroaryl; wherein the R⁴ 5-11 membered heteroaryl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; wherein L¹ isabsent, or is selected from the group consisting of C₁-C₆ alkylene,C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein theL¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or aspart of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo.

In one embodiment of Formula (II), R⁴ is selected from the groupconsisting of (C₁-C₆ alkylene)_(x)-C₉-C₁₀ aryl, (C₁-C₆alkylene)_(x)-5-11 membered heteroaryl, (C₁-C₆ alkylene)_(x)-4-12membered heterocyclyl, (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl, and(C₁-C₆ alkylene)_(x)-C₄-C₁₁ cycloalkenyl; wherein the R⁴ C₆-C₁₀ memberedaryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl, the 5-11 memberedheteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl, the 4-12membered heterocyclyl of (C₁-C₆ alkylene)_(x)-4-12 memberedheterocyclyl, the C₃-C₁₁ cycloalkyl of (C₁-C₆ alkylene)_(x)-C₃-C₁₁cycloalkyl, and the C₄-C₁₁ cycloalkenyl of (C₁-C₆ alkylene)_(x)-C₄-C₁₁cycloalkenyl are optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, C(O)OR⁹,C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl,Br and I; and x is 0 or 1. In another embodiment of Formula (II), R⁴ isselected from the group consisting of (C₁-C₆ alkylene)_(x)-C₆-C₁₀- aryl,(C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl, (C₁-C₆ alkylene)_(x)-4-12membered heterocyclyl, and (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl;wherein the R⁴ C₆-C₁₀ membered aryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀membered aryl, the 5-11 membered heteroaryl of (C₁-C₆ alkylene)_(x)-5-11membered heteroaryl, the 4-12 membered heterocyclyl of (C₁-C₆alkylene)_(x)-4-12 membered heterocyclyl, and the C₃-C₁₁ cycloalkyl of(C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl are optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0 or 1. Inanother embodiment of Formula (II), R⁴ is (C₁-C₆ alkylene)_(x)-C₆-C₁₀aryl; wherein the R⁴ (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;and x is 0 or 1.

In another embodiment of Formula (II), R⁴ is (C₁-C₆ alkylene)_(x)-5-11membered heteroaryl; wherein the R⁴ (C₁-C₆ alkylene)_(x)-5-11 memberedheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹,OH, Cl, and Br; and x is 0 or 1. In another embodiment of Formula (II),R⁴ is (C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl; wherein the R⁴(C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0or 1. In another embodiment of Formula (II), R⁴ is (C₁-C₆alkylene)_(x)-C₃-C₁₁ cycloalkyl; wherein the R⁴ (C₁-C₆alkylene)_(x)-C₃-C₁₁ cycloalkyl is optionally substituted with one ormore substituents independently selected from the group consisting ofR⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0 or 1.

In one embodiment of Formula (II), R⁵ is selected from the groupconsisting of C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, 4-6membered monocyclic heterocycle fused to a phenyl group, C₃-C₁₁cycloalkyl, and C₄-C₁₁ cycloalkenyl; wherein the R⁵ C₆-C₁₀ memberedaryl, 5-11 membered heteroaryl, 4-6 membered monocyclic heterocyclefused to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁cycloalkenyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹², OR¹², NR¹³R¹⁴, OH, oxo, CN,NO₂, F, Cl, Br and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹² 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, OH, oxo, CN, NO₂, F, Cl,Br and I; and R¹³ and R¹⁴, at each occurrence, are each independentlyhydrogen or C₁-C₆ alkyl. In another embodiment of Formula (II), R⁵ isselected from the group consisting of C₆-C₁₀ membered aryl, 5-11membered heteroaryl, and 4-6 membered monocyclic heterocycle fused to aphenyl group; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11 memberedheteroaryl, and 4-6 membered monocyclic heterocycle fused to a phenylgroup are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,F, Cl, Br, and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F,and Cl; and R¹³ and R¹⁴, at each occurrence, are each independentlyC₁-C₆ alkyl. In another embodiment of Formula (II), R⁵ is selected fromthe group consisting of C₆-C₁₀ membered aryl and 5-11 memberedheteroaryl; wherein the R⁵ C₆-C₁₀ membered aryl and 5-11 memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,F, Cl, Br, and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more independently selected C₁-C₆alkyl; and R¹³ and R¹⁴, at each occurrence, are each independently C₁-C₆alkyl.

In another embodiment of Formula (II), R⁵ is C₆-C₁₀ membered aryl;wherein the R⁵ C₆-C₁₀ membered aryl is optionally substituted with oneor more substituents independently selected from the group consisting ofR¹², OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F, and Cl; and R¹³ and R¹⁴, ateach occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (II), R⁵ is 5-11 membered heteroaryl; wherein theR⁵ 5-11 membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F, and Cl; and R¹³ and R¹⁴,at each occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (II), R⁵ is 5-11 membered heteroaryl; wherein theR⁵ 5-11 membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂,oxo, CN, F, and Cl; and R¹³ and R¹⁴, at each occurrence, are eachindependently C₁-C₆ alkyl. In another embodiment of Formula (II), R⁵ is5-11 membered heteroaryl; wherein the R⁵ 5-11 membered heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, and Br;R¹², at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;wherein each R¹² 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more independently selected C₁-C₆ alkyl; and R¹³and R¹⁴, at each occurrence, are each independently C₁-C₆ alkyl. Inanother embodiment of Formula (II), R⁵ is phenyl, which isunsubstituted. In another embodiment of Formula (II), R⁵ is phenyl;wherein the R⁵ phenyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, and Br; R¹², at each occurrence, is independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12membered heterocyclyl; and R¹³ and R¹⁴, at each occurrence, are eachindependently C₁-C₆ alkyl. In another embodiment of Formula (II), R⁵ isphenyl; which is substituted with one R¹²; and R¹² is C₁-C₆ alkyl,C₃-C₁₁ cycloalkyl, or F. In another embodiment of Formula (II), R⁵ isphenyl; which is substituted with one R¹²; and R¹² is CH₃, CH₂CH₃ orCH(CH₃)₂. In another embodiment of Formula (II), R⁵ is phenyl; which issubstituted with one R¹²; and R¹² is cyclopropyl. In another embodimentof Formula (II), R⁵ is pyridinyl; which is substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², and NR¹³R¹⁴; R¹² is independently C₁-C₆ alkyl; and R¹³ and R¹⁴, ateach occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (II), R⁵ is pyridinyl; which is substituted withone or more substituents independently selected from the groupconsisting of R¹², OR¹², and NR¹³R¹⁴; R¹² is independently CH₃ orCH(CH₃)₂; and R¹³ and R¹⁴, at each occurrence, are each independentlyCH₃. In another embodiment of Formula (II), R⁵ is pyridinyl; wherein theR⁵ pyridinyl is optionally substituted with one or more independentlyselected R¹²; and R¹², at each occurrence, is independently C₁-C₆ alkyl.

In one embodiment of Formula (II), R⁶ is selected from the groupconsisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl,and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or moresubstituents independently selected from the group consisting of R¹⁵,OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br and I; wherein the R⁶ 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl are optionally substitutedwith one or more substituents independently selected from the groupconsisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸, NR¹⁹R²⁰,OH, oxo, CN, NO₂, F, Cl, Br and I; R¹⁵ at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I; R¹⁶ and R¹⁷, at eachoccurrence, are each independently hydrogen or C₁-C₆ alkyl; and R¹⁸, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (II), R⁶ is selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; whereinthe R⁶ C₁-C₆ alkyl is optionally substituted with one or moreindependently selected R¹⁵ or F; wherein the R⁶ 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclylare optionally substituted with one or more substituents independentlyselected from the group consisting of R¹⁸ and OR¹⁸; R¹⁵, at eachoccurrence, is independently C₃-C₁₁ cycloalkyl; and R¹⁸, at eachoccurrence, is independently selected C₁-C₆ alkyl; wherein each R¹⁸C₁-C₆ alkyl is optionally substituted with one or more F. In oneembodiment of Formula (II), R⁶ is C₁-C₆ alkyl; wherein the R⁶ C₁-C₆alkyl is optionally substituted with one or more independently selectedR¹⁵; and R¹⁵, at each occurrence, is independently C₃-C₁₁ cycloalkyl. Inanother embodiment of Formula (II), R⁶ is C₁-C₆ alkyl; wherein the R⁶C₁-C₆ alkyl is unsubstituted. In another embodiment of Formula (II), R⁶is —CH₂CH₃. In another embodiment of Formula (II), R⁶ is —CH(CH₃)₂. Inone embodiment of Formula (II), R⁶ is 4-12 membered heterocyclyl;wherein the R⁶ 4-12 membered heterocyclyl is optionally substituted withone or more substituents independently selected from the groupconsisting of OR¹⁸; and R¹⁸, at each occurrence, is independently C₁-C₆alkyl. In another embodiment of Formula (II), R⁶ is 4-12 memberedheterocyclyl; wherein the R⁶ 4-12 membered heterocyclyl isunsubstituted. In another embodiment of Formula (II), R⁶ istetrahydrofuranyl. In another embodiment of Formula (II), R⁶ istetrahydropyranyl. In one embodiment of Formula (II), R⁶ is C₃-C₁₁cycloalkyl; wherein the R⁶ C₃-C₁₁ cycloalkyl is optionally substitutedwith one or more independently selected OR¹⁸; and R¹⁸, at eachoccurrence, is independently selected C₁-C₆ alkyl. In one embodiment ofFormula (II), R⁶ is cyclohexyl; wherein the R⁶ cyclohexyl isunsubstituted.

In one embodiment of Formula (II), R¹ is C(O)OR⁶; and R⁶ is C₁-C₆ alkylor C₃-C₁₁ cycloalkyl. In one embodiment of Formula (II), R¹ is C(O)OR⁶;and R⁶ is C₁-C₆ alkyl; wherein the R⁶ is C₁-C₆ unsubstituted alkyl.

In one embodiment of Formula (II), R¹ is C(O)R⁶; R⁶ is 4-12 memberedheterocyclyl; wherein the R⁶ 4-12 membered heterocyclyl is optionallysubstituted with OR¹⁸; and R¹⁸, at each occurrence, is independentlyselected C₁-C₆ alkyl. In one embodiment of Formula (II), R¹ is C(O)R⁶;and R⁶ is 4-12 membered heterocyclyl; wherein the R⁶ 4-12 memberedheterocyclyl is unsubstituted. In one embodiment of Formula (II), R¹ isC(O)R⁶; and R⁶ is C₃-C₁₁ cycloalkyl; wherein the R⁶ C₃-C₁₁ cycloalkyl isunsubstituted.

In one embodiment of Formula (II), R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R²¹, OR²¹, C(O)R²¹, OC(O)R²¹,C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH, oxo, CN, NO₂, F, Cl, Br andI; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I; R²¹, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;R²² and R²³, at each occurrence, are each independently hydrogen orC₁-C₆ alkyl; R²⁴, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy- C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; and R²⁵ and R²⁶, at each occurrence, are eachindependently hydrogen or C₁-C₆ alkyl. In another embodiment of Formula(II), R⁹, at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁ cycloalkyl, and4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more CN or F; wherein each R⁹ 6-10 memberedaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R²⁴, OR²⁴, and F; and R²⁴, at each occurrence,is independently C₁-C₆ alkyl.

In one embodiment of Formula (II), R¹⁰ and R¹¹, at each occurrence, areeach independently selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl, and 5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹phenyl and 5-6 membered heteroaryl is optionally substituted with one ormore substituents independently selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br,and I. In another embodiment of Formula (II), R¹⁰ and R¹¹, at eachoccurrence, are each independently C₁-C₆ alkyl.

In one embodiment of Formula (II), R⁴ is L¹-C₆-C₁₀ aryl; wherein the R⁴C₆-C₁₀ aryl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹ and OR⁹; L¹ isabsent or is C₁-C₆ alkylene; and R⁹, at each occurrence, isindependently selected C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl isoptionally substituted with one or more F. In one embodiment of Formula(II), R⁴ is (C₁-C₆ alkylene)_(x)-C₆-C₁₀ aryl; wherein the R⁴ (C₁-C₆alkylene)_(x)-C₆-C₁₀ membered aryl is optionally substituted with one ormore substituents independently selected from the group consisting of R⁹and OR⁹; x is 0 or 1; and R⁹, at each occurrence, is independentlyselected C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more F. In another embodiment of Formula (II),R⁴ is CH₂-phenyl; wherein the R⁴ CH₂-phenyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹ and OR⁹; and R⁹, at each occurrence, is independentlyselected from the group consisting of CH₃ and CF₃. In another embodimentof Formula (II), R⁴ is L¹-5-11 membered heteroaryl; wherein the R⁴ 5-11membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹ andOR⁹; L¹ is absent, or is C₁-C₆ alkylene; and R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl andC₃-C₁₁ cycloalkyl; wherein each R⁹ C₁-C₆ alkyl is optionally substitutedwith one or more F.

In another embodiment of Formula (II), R⁴ is (C₁-C₆ alkylene)_(x)-5-11membered heteroaryl; wherein the R⁴ (C₁-C₆ alkylene)_(x)-5-11 memberedheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹ and OR⁹; x is 0or 1; and R⁹, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl and C₃-C₁₁ cycloalkyl; wherein each R⁹C₁-C₆ alkyl is optionally substituted with one or more F. In anotherembodiment of Formula (II), R⁴ is CH₂-pyridinyl; wherein the R⁴ CH₂—pyridinyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹ and OR⁹; and R⁹,at each occurrence, is independently selected from the group consistingof CH₃, C(CH₃)₃, CF₃, and cyclobutyl. In another embodiment of Formula(II), R⁴ is CH₂-quinolinyl; wherein the R⁴ CH₂— quinolinyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹ and OR⁹; and R⁹, at each occurrence, isindependently CH₃.

In one embodiment of Formula (II), R⁴ is selected from the groupconsisting of

wherein R^(x) is OCH₃, and R^(y) is selected from the group consistingof CF₃, C(CH₃)₃, and cyclobutyl; and n is 1.

One embodiment pertains to compounds of Formula (II),

wherein

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof,    -   R^(2A) is hydrogen;    -   R³ is C₁-C₆ alkyl; wherein the R³ C₁-C₆ alkyl is optionally        substituted with one or more C₁-C₆ alkoxy;    -   R^(3A) is hydrogen;    -   R⁴ is selected from the group consisting of L¹-C₆-C₁₀ aryl and        L¹-5-11 membered heteroaryl; wherein the R⁴ C₆-C₁₀ aryl and 5-11        membered heteroaryl are optionally substituted with one or more        substituents independently selected from the group consisting of        R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;    -   L¹ is absent, or is selected from the group consisting of C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆        alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene,        and C₂-C₆ alkynylene, alone or as part of a group, are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, OH, and oxo;    -   R is selected from the group consisting of C₆-C₁₀ membered aryl,        5-11 membered heteroaryl, and 4-6 membered monocyclic        heterocycle fused to a phenyl group; wherein the R⁵ C₆-C₁₀        membered aryl, 5-11 membered heteroaryl, and 4-6 membered        monocyclic heterocycle fused to a phenyl group are optionally        substituted with one or more substituents independently selected        from the group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, Br and        I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆        alkyl is optionally substituted with one or more substituents        independently selected from the group consisting of R¹⁵, and F;        wherein the R⁶ 5-11 membered heteroaryl and C₃-C₁₁ cycloalkyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R¹⁸ and        OR¹⁸;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        CN, and F; wherein each R⁹ 6-10 membered aryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, and F;    -   R¹⁰ and R¹¹, at each occurrence, are each independently C₁-C₆        alkyl;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12        membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11        membered heteroaryl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆        alkyl)₂, oxo, CN, F, and Cl;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently C₃-C₁₁ cycloalkyl;    -   R¹⁸, at each occurrence, is independently C₁-C₆ alkyl; wherein        each R¹⁸ C₁-C₆ alkyl is optionally substituted with one or more        F; and    -   R²⁴, at each occurrence, is independently C₁-C₆ alkyl.

In one embodiment of Formula (II),

-   -   R¹ is selected from the group consisting of C(O)R⁶, C(O)OR⁶, and        C(O)NR⁷R⁸;    -   R² is C(O)OH or a bioisostere thereof;    -   R^(2A) is hydrogen;    -   R³ is C₁-C₆ alkyl;    -   R^(3A) is hydrogen;    -   R⁴ is selected from the group consisting of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ aryl and (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl; wherein the R⁴ C₆-C₁₀ membered aryl of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ membered aryl, and the 5-11 membered        heteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        NR¹⁰R¹¹, OH, Cl, and Br;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered aryl        and 5-11 membered heteroaryl; wherein the R⁵ C₆-C₁₀ membered        aryl and 5-11 membered heteroaryl are optionally substituted        with one or more substituents independently selected from the        group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, and Br;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;        wherein the R⁶ C₁-C₆ alkyl is optionally substituted with one or        more independently selected R¹⁵; wherein the R⁶ 6C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl are optionally        substituted with one or more independently selected OR¹⁸;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹        C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally        substituted with one or more F; wherein each R⁹ 6-10 membered        C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, and F;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        C₁-C₆ alkyl;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12        membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered        heterocyclyl is optionally substituted with one or more        independently selected from the group consisting of C₁-C₆ alkyl;    -   R¹³ and R¹⁴, at each occurrence, are each independently C₁-C₆        alkyl;    -   R¹⁵, at each occurrence, is independently selected C₃-C₁₁        cycloalkyl;    -   R¹⁸, at each occurrence, is independently selected C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected C₁-C₆ alkyl;        and    -   x is 0 or 1.

Exemplary compounds of Formula (II) include, but are not limited to

-   (2S*,3R*,4S*,5S*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(2-methoxyethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-N-(1-methylcyclopropane-1-sulfonyl)-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(cyclopropanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(ethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(dimethylsulfamoyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(methanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclohexyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexane    carbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexane    carbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluoro-4-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(4-fluoro-2-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2,4-difluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(4-methylphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(3-chiorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(piperidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoroazetidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoropyrrolidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(prop-2-en-1-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-cyclobutyl-5-methoxypyridin-4-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]phenyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(3,6-dihydro-2H-pyran-4-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-(oxane-4-carbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(oxane-4-carbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(oxane-4-carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-1-(ethoxycarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-[2-(difluoromethyl)phenyl]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2,6-difluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-([1,1′-biphenyl]-2-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-cyanopropan-2-yl)-2-methoxyphenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrazol-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[3′-(dimethylamino)    [1,1′-biphenyl]-2-yl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2′-methyl[1,1′-biphenyl]-2-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyridin-4-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyrimidin-5-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(furan-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrrol-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[3′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-[2-(2H-1,3-benzodioxol-5-yl)phenyl]-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(6-methoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[4′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-cyano[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-{2-[6-(trifluoromethyl)pyridin-3-yl]phenyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(5-ethoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(1-benzofuran-7-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(2-methylpropyl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(6-methoxypyridine-2-sulfonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopropyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-7-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethoxy)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)—N-(6-aminopyridine-2-sulfonyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxamide;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-3-methoxypyridin-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({[2-methoxy-5-(trifluoromethyl)pyridin-3-yl](²H₂)methyl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)pyridin-3-yl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)phenyl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[(5-tert-butyl-2-methoxyphenyl)(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-chloro-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-6,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-8-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({2-[2-methoxy-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-1-(cyclohexanecarbonyl)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxoethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-{[(1,1,1-trifluoropropan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2R)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-hydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-methoxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-3-(2-methoxypropan-2-yl)-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopropane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopentane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-4-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]propoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-iodo-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1R,2R)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1S,2S)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[(5-chloro-2-methoxypyridin-3-yl)oxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(²H₃)methylphenyl]-1-[(2S,3S)-(2,3-²H₂)oxane-2-carbonyl](2-²H)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenoxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-1-benzofuran-2-yl)methoxy]-3-tert-butyl-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]-4-{[7-(trifluoromethyl)-1-benzofuran-2-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-1-benzofuran-2-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(naphthalene-1-sulfonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-1-benzofuran-2-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid; and pharmaceutically acceptable salts thereof.

Formula (III)

One embodiment pertains to compounds of Formula (III)

wherein

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R⁴ is selected from the group consisting of L¹-C₆-C₁₀ aryl,        L¹-5-11 membered heteroaryl, L¹-4-12 membered heterocyclyl,        L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl; wherein the R⁴        C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 membered        heterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH,        oxo, CN, NO₂, F, Cl, Br and I;    -   L¹ is absent, or is selected from the group consisting of C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆        alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene,        and C₂-C₆ alkynylene, alone or as part of a group, are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, OH, and oxo;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, 4-6 membered monocyclic        heterocycle fused to a phenyl group, C₃-C₁₁ cycloalkyl, and        C₄-C₁₁ cycloalkenyl; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11        membered heteroaryl, 4-6 membered monocyclic heterocycle fused        to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br        and I; wherein the R⁶ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸,        NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R²¹, OR²¹,        C(O)R²¹, OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH,        oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,        C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and        5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6        membered heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,        N(C₁-C₆ alkyl)₂, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹⁵ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo,        OH, CN, NO₂, F, Cl, Br and I;    -   R¹⁶ and R¹⁷, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁸, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl,        Br and I;    -   R¹⁹ and R²⁰, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I;    -   R²² and R²³, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy-        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; and    -   R²⁵ and R²⁶, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl.

In one embodiment of Formula (III),

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R⁴ is selected from the group consisting of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ aryl, (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl, (C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl,        (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl, and (C₁-C₆        alkylene)_(x)-C₄-C₁₁ cycloalkenyl; wherein the R⁴ C₆-C₁₀        membered aryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl, the        5-11 membered heteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl, the 4-12 membered heterocyclyl of (C₁-C₆        alkylene)_(x)-4-12 membered heterocyclyl, the C₃-C₁₁ cycloalkyl        of (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl, and the C₄-C₁₁        cycloalkenyl of (C₁-C₆ alkylene)_(x)-C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH,        oxo, CN, NO₂, F, Cl, Br and I;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁        cycloalkenyl; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are        optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br        and I; wherein the R⁶ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸,        NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R²¹, OR²¹,        C(O)R²¹, OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH,        oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,        C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and        5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6        membered heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F,        Cl, Br and I;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹⁵ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo,        OH, CN, NO₂, F, Cl, Br and I;    -   R¹⁶ and R¹⁷, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁸, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl,        Br and I;    -   R¹⁹ and R²⁰, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I;    -   R²² and R²³, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy-        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl;    -   R²⁵ and R²⁶, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl; and    -   x is 0 or 1.

In one embodiment of Formula (III), R¹ is selected from the groupconsisting of SO₂R⁶, C(O)R⁶, C(O)OR⁶, and C(O)NR⁷R⁸. In anotherembodiment of Formula (III), R¹ is C(O)R⁶ or C(O)OR⁶. In anotherembodiment of Formula (III), R¹ is SO₂R⁶. In another embodiment ofFormula (III), R¹ is C(O)R⁶. In another embodiment of Formula (III), R¹is C(O)OR⁶. In another embodiment of Formula (III), R¹ is C(O)NR⁷R⁸.

In one embodiment of Formula (III), R⁴ is selected from the groupconsisting of L¹-C₆-C₁₀ aryl, L¹-5-11 membered heteroaryl, L¹-4-12membered heterocyclyl, L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl;wherein the R⁴ C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 memberedheterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹,Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein L¹ isabsent, or is selected from the group consisting of C₁-C₆ alkylene,C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein theL¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or aspart of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo. In another embodiment of Formula (III), R⁴ isselected from the group consisting of L¹-C₆-C₁₀ aryl, and L¹-5-11membered heteroaryl; wherein the R⁴ C₆-C₁₀ aryl, and 5-11 memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹,OH, Cl, and Br; wherein L¹ is absent, or is selected from the groupconsisting of C₁-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, andC₁-C₆ alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, andC₂-C₆ alkynylene, alone or as part of a group, are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆ alkoxy, OH, and oxo. In another embodimentof Formula (III), R⁴ is L¹-C₆-C₁₀ aryl; wherein the R⁴ C₆-C₁₀ aryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;wherein L¹ is absent, or is selected from the group consisting of C₁-C₆alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—;wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene,alone or as part of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo.

In another embodiment of Formula (III), R⁴ is L¹-5-11 memberedheteroaryl; wherein the R⁴ 5-11 membered heteroaryl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; wherein L¹ isabsent, or is selected from the group consisting of C₁-C₆ alkylene,C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein theL¹ C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or aspart of a group, are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, OH, and oxo.

In one embodiment of Formula (III), R⁴ is selected from the groupconsisting of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ aryl, (C₁-C₆alkylene)_(x)-5-11 membered heteroaryl, (C₁-C₆ alkylene)_(x)-4-12membered heterocyclyl, (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl, and(C₁-C₆ alkylene)_(x)-C₄-C₁₁ cycloalkenyl; wherein the R⁴ C₆-C₁₀ memberedaryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl, the 5-11 memberedheteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl, the 4-12membered heterocyclyl of (C₁-C₆ alkylene)_(x)-4-12 memberedheterocyclyl, the C₃-C₁₁ cycloalkyl of (C₁-C₆ alkylene)_(x)-C₃-C₁₁cycloalkyl, and the C₄-C₁₁ cycloalkenyl of (C₁-C₆ alkylene)_(x)-C₄-C₁₁cycloalkenyl are optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, C(O)OR⁹,C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹, Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl,Br and I; and x is 0 or 1. In another embodiment of Formula (III), R⁴ isselected from the group consisting of (C₁-C₆ alkylene)_(x)-C₆-C₁₀ aryl,(C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl, (C₁-C₆ alkylene)_(x)-4-12membered heterocyclyl, and (C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl;wherein the R⁴ C₆-C₁₀ membered aryl of (C₁-C₆ alkylene)_(x)-C₆-C₁₀membered aryl, the 5-11 membered heteroaryl of (C₁-C₆ alkylene)_(x)-5-11membered heteroaryl, the 4-12 membered heterocyclyl of (C₁-C₆alkylene)_(x)-4-12 membered heterocyclyl, and the C₃-C₁₁ cycloalkyl of(C₁-C₆ alkylene)_(x)-C₃-C₁₁ cycloalkyl are optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0 or 1. Inanother embodiment of Formula (III), R⁴ is (C₁-C₆ alkylene)_(x)-C₆-C₁₀aryl; wherein the R⁴ (C₁-C₆ alkylene)_(x)-C₆-C₁₀ membered aryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;and x is 0 or 1.

In another embodiment of Formula (III), R⁴ is (C₁-C₆ alkylene)_(x)-5-11membered heteroaryl; wherein the R⁴ (C₁-C₆ alkylene)_(x)-5-11 memberedheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, NR¹⁰R¹¹,OH, Cl, and Br; and x is 0 or 1. In another embodiment of Formula (III),R⁴ is (C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl; wherein the R⁴(C₁-C₆ alkylene)_(x)-4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0or 1. In another embodiment of Formula (III), R⁴ is (C₁-C₆alkylene)_(x)-C₃-C₁₁ cycloalkyl; wherein the R⁴ (C₁-C₆alkylene)_(x)-C₃-C₁₁ cycloalkyl is optionally substituted with one ormore substituents independently selected from the group consisting ofR⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br; and x is 0 or 1.

In one embodiment of Formula (III), R⁵ is selected from the groupconsisting of C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, 4-6membered monocyclic heterocycle fused to a phenyl group, C₃-C₁₁cycloalkyl, and C₄-C₁₁ cycloalkenyl; wherein the R⁵ C₆-C₁₀ memberedaryl, 5-11 membered heteroaryl, 4-6 membered monocyclic heterocyclefused to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁cycloalkenyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹², OR¹², NR¹³R¹⁴, OH, oxo, CN,NO₂, F, Cl, Br and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹² 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, OH, oxo, CN, NO₂, F, Cl,Br and I; and R¹³ and R¹⁴, at each occurrence, are each independentlyhydrogen or C₁-C₆ alkyl. In another embodiment of Formula (III), R⁵ isselected from the group consisting of C₆-C₁₀ membered aryl, 5-11membered heteroaryl, and 4-6 membered monocyclic heterocycle fused to aphenyl group; wherein the R⁵ C₆-C₁₀ membered aryl, 5-11 memberedheteroaryl, and 4-6 membered monocyclic heterocycle fused to a phenylgroup are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,F, Cl, Br, and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F,and Cl; and R¹³ and R¹⁴, at each occurrence, are each independentlyC₁-C₆ alkyl. In another embodiment of Formula (III), R⁵ is selected fromthe group consisting of C₆-C₁₀ membered aryl and 5-11 memberedheteroaryl; wherein the R⁵ C₆-C₁₀ membered aryl and 5-11 memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹², OR¹², NR¹³R¹⁴,F, Cl, Br, and I; R¹², at each occurrence, is independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more independently selected C₁-C₆alkyl; and R¹³ and R¹⁴, at each occurrence, are each independently C₁-C₆alkyl.

In another embodiment of Formula (III), R⁵ is C₆-C₁₀ membered aryl;wherein the R⁵ C₆-C₁₀ membered aryl is optionally substituted with oneor more substituents independently selected from the group consisting ofR¹², OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F, and Cl; and R¹³ and R¹⁴, ateach occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (III), R⁵ is 5-11 membered heteroaryl; wherein theR⁵ 5-11 membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂, oxo, CN, F, and Cl; and R¹³ and R¹⁴,at each occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (III), R⁵ is 5-11 membered heteroaryl; wherein theR⁵ 5-11 membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, Br, and I; R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆haloalkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂,oxo, CN, F, and Cl; and R¹³ and R¹⁴, at each occurrence, are eachindependently C₁-C₆ alkyl. In another embodiment of Formula (III), R⁵ is5-11 membered heteroaryl; wherein the R⁵ 5-11 membered heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, and Br;R¹², at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;wherein each R¹² 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more independently selected C₁-C₆ alkyl; and R¹³and R¹⁴, at each occurrence, are each independently C₁-C₆ alkyl. Inanother embodiment of Formula (III), R⁵ is phenyl, which isunsubstituted. In another embodiment of Formula (III), R⁵ is phenyl;wherein the R⁵ phenyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², NR¹³R¹⁴, F, Cl, and Br; R¹², at each occurrence, is independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12membered heterocyclyl; and R¹³ and R¹⁴, at each occurrence, are eachindependently C₁-C₆ alkyl. In another embodiment of Formula (III), R⁵ isphenyl; which is substituted with one R¹²; and R¹² is C₁-C₆ alkyl,C₃-C₁₁ cycloalkyl, or F. In another embodiment of Formula (III), R⁵ isphenyl; which is substituted with one R¹²; and R¹² is CH₃, CH₂CH₃ orCH(CH₃)₂. In another embodiment of Formula (III), R⁵ is phenyl; which issubstituted with one R¹²; and R¹² is cyclopropyl. In another embodimentof Formula (III), R⁵ is pyridinyl; which is substituted with one or moresubstituents independently selected from the group consisting of R¹²,OR¹², and NR¹³R¹⁴; R¹² is independently C₁-C₆ alkyl; and R¹³ and R¹⁴, ateach occurrence, are each independently C₁-C₆ alkyl. In anotherembodiment of Formula (III), R⁵ is pyridinyl; which is substituted withone or more substituents independently selected from the groupconsisting of R¹², OR¹², and NR¹³R¹⁴; R¹² is independently CH₃ orCH(CH₃)₂; and R¹³ and R¹⁴, at each occurrence, are each independentlyCH₃. In another embodiment of Formula (III), R⁵ is pyridinyl; whereinthe R⁵ pyridinyl is optionally substituted with one or moreindependently selected R¹²; and R¹², at each occurrence, isindependently C₁-C₆ alkyl.

In one embodiment of Formula (III), R⁶ is selected from the groupconsisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl,and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or moresubstituents independently selected from the group consisting of R¹⁵,OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br and I; wherein the R⁶ 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl are optionally substitutedwith one or more substituents independently selected from the groupconsisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸, C(O)OR¹⁸, SO₂R¹⁸, NR¹⁹R²⁰,OH, oxo, CN, NO₂, F, Cl, Br and I; R¹⁵ at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I; R¹⁶ and R¹⁷, at eachoccurrence, are each independently hydrogen or C₁-C₆ alkyl; and R¹⁸, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (III), R⁶ is selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁cycloalkyl, and 4-12 membered heterocyclyl; whereinthe R⁶ C₁-C₆ alkyl is optionally substituted with one or moreindependently selected R¹⁵ or F; wherein the R⁶ 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclylare optionally substituted with one or more substituents independentlyselected from the group consisting of R¹⁸ and OR¹⁸; R¹⁵, at eachoccurrence, is independently C₃-C₁₁ cycloalkyl; and R¹⁸, at eachoccurrence, is independently selected C₁-C₆ alkyl; wherein each R¹⁸C₁-C₆ alkyl is optionally substituted with one or more F. In oneembodiment of Formula (III), R⁶ is C₁-C₆ alkyl; wherein the R⁶ C₁-C₆alkyl is optionally substituted with one or more independently selectedR¹⁵; and R¹⁵, at each occurrence, is independently C₃-C₁₁ cycloalkyl. Inanother embodiment of Formula (III), R⁶ is C₁-C₆ alkyl; wherein the R⁶C₁-C₆ alkyl is unsubstituted. In another embodiment of Formula (III), R⁶is —CH₂CH₃. In another embodiment of Formula (III), R⁶ is —CH(CH₃)₂. Inone embodiment of Formula (III), R⁶ is 4-12 membered heterocyclyl;wherein the R⁶ 4-12 membered heterocyclyl is optionally substituted withone or more substituents independently selected from the groupconsisting of OR¹⁸; and R¹⁸, at each occurrence, is independently C₁-C₆alkyl. In another embodiment of Formula (III), R⁶ is 4-12 memberedheterocyclyl; wherein the R⁶ 4-12 membered heterocyclyl isunsubstituted. In another embodiment of Formula (III), R⁶ istetrahydrofuranyl. In another embodiment of Formula (III), R⁶ istetrahydropyranyl. In one embodiment of Formula (III), R⁶ is C₃-C₁₁cycloalkyl; wherein the R⁶ C₃-C₁₁ cycloalkyl is optionally substitutedwith one or more independently selected OR¹⁸; and R¹⁸, at eachoccurrence, is independently selected C₁-C₆ alkyl. In one embodiment ofFormula (III), R⁶ is cyclohexyl; wherein the R⁶ cyclohexyl isunsubstituted.

In one embodiment of Formula (III), R¹ is C(O)OR⁶; and R⁶ is C₁-C₆ alkylor C₃-C₁₁ cycloalkyl. In one embodiment of Formula (III), R¹ is C(O)OR⁶;and R⁶ is C₁-C₆ alkyl; wherein the R⁶ is C₁-C₆ unsubstituted alkyl.

In one embodiment of Formula (III), R¹ is C(O)R⁶; R⁶ is 4-12 memberedheterocyclyl; wherein the R⁶ 4-12 membered heterocyclyl is optionallysubstituted with OR¹⁸; and R¹⁸, at each occurrence, is independentlyselected C₁-C₆ alkyl. In one embodiment of Formula (III), R¹ is C(O)R⁶;and R⁶ is 4-12 membered heterocyclyl; wherein the R⁶ 4-12 memberedheterocyclyl is unsubstituted. In one embodiment of Formula (III), R¹ isC(O)R⁶; and R⁶ is C₃-C₁₁ cycloalkyl; wherein the R⁶ C₃-C₁₁ cycloalkyl isunsubstituted.

In one embodiment of Formula (III), R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R²¹, OR²¹, C(O)R²¹, OC(O)R²¹,C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH, oxo, CN, NO₂, F, Cl, Br andI; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R²⁴, OR²⁴, C(O)R²⁴, OC(O)R²⁴,C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I; R²¹, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;R²² and R²³, at each occurrence, are each independently hydrogen orC₁-C₆ alkyl; R²⁴, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy- C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; and R²⁵ and R²⁶, at each occurrence, are eachindependently hydrogen or C₁-C₆ alkyl. In another embodiment of Formula(III), R⁹, at each occurrence, is independently selected from the groupconsisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁ cycloalkyl, and4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more CN or F; wherein each R⁹ 6-10 memberedaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R²⁴, OR²⁴, and F; and R²⁴, at each occurrence,is independently C₁-C₆ alkyl.

In one embodiment of Formula (III), R¹⁰ and R¹¹, at each occurrence, areeach independently selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl, and 5-6 membered heteroaryl; wherein each R¹⁰ and R¹¹phenyl and 5-6 membered heteroaryl is optionally substituted with one ormore substituents independently selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br,and I. In another embodiment of Formula (III), R¹⁰ and R¹¹, at eachoccurrence, are each independently C₁-C₆ alkyl.

In one embodiment of Formula (III), R⁴ is L¹-C₆-C₁₀ aryl; wherein the R⁴C₆-C₁₀ aryl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹ and OR⁹; L¹ isabsent, or is C₁-C₆ alkylene; and R⁹, at each occurrence, isindependently selected C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl isoptionally substituted with one or more F. In one embodiment of Formula(III), R⁴ is (C₁-C₆ alkylene)_(x)-C₆-C₁₀ aryl; wherein the R⁴ (C₁-C₆alkylene)_(x)-C₆-C₁₀ membered aryl is optionally substituted with one ormore substituents independently selected from the group consisting of R⁹and OR⁹; x is 0 or 1; and R⁹, at each occurrence, is independentlyselected C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more F. In another embodiment of Formula (III),R⁴ is CH₂-phenyl; wherein the R⁴ CH₂-phenyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹ and OR⁹; and R⁹, at each occurrence, is independentlyselected from the group consisting of CH₃ and CF₃. In another embodimentof Formula (III), R⁴ is L¹-5-11 membered heteroaryl; wherein the R⁴ 5-11membered heteroaryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹ andOR⁹; L¹ is absent, or is C₁-C₆ alkylene; and R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl andC₃-C₁₁ cycloalkyl; wherein each R⁹ C₁-C₆ alkyl is optionally substitutedwith one or more F. In another embodiment of Formula (III), R⁴ is (C₁-C₆alkylene)_(x)-5-11 membered heteroaryl; wherein the R⁴ (C₁-C₆alkylene)_(x)-5-11 membered heteroaryl is optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹ and OR⁹; x is 0 or 1; and R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl andC₃-C₁₁ cycloalkyl; wherein each R⁹ C₁-C₆ alkyl is optionally substitutedwith one or more F. In another embodiment of Formula (III), R⁴ isCH₂-pyridinyl; wherein the R⁴ CH₂— pyridinyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹ and OR⁹; and R⁹, at each occurrence, is independentlyselected from the group consisting of CH₃, C(CH₃)₃, CF₃, and cyclobutyl.In another embodiment of Formula (III), R⁴ is CH₂-quinolinyl; whereinthe R⁴ CH₂-quinolinyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹ andOR⁹; and R⁹, at each occurrence, is independently CH₃.

In one embodiment of Formula (III), R⁴ is selected from the groupconsisting of

wherein R^(x) is OCH₃, and R^(y) is selected from the group consistingof CF₃, C(CH₃)₃, and cyclobutyl; and n is 1.

One embodiment pertains to compounds of Formula (III),

wherein

-   -   R¹ is C(O)R⁶;    -   R⁴ is L¹-5-11 membered heteroaryl; wherein the R⁴ 5-11 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        R⁹ and OR⁹;    -   L¹ is C₁-C₆ alkylene;    -   R is C₆-C₁₀ membered aryl; wherein the R⁵ C₆-C₁₀ membered aryl        is optionally substituted with one or more R¹²;    -   R⁶ is 4-12 membered heterocyclyl;    -   R⁹, at each occurrence, is independently selected C₁-C₆ alkyl;        wherein each R⁹ C₁-C₆ alkyl is optionally substituted with one        or more F; and    -   R¹², at each occurrence, is independently selected C₁-C₆ alkyl.

One embodiment pertains to compounds of Formula (III),

wherein

-   -   R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,        C(O)OR⁶, and C(O)NR⁷R⁸;    -   R⁴ is selected from the group consisting of L¹-C₆-C₁₀ aryl and        L¹-5-11 membered heteroaryl; wherein the R⁴ C₆-C₁₀ aryl and 5-11        membered heteroaryl are optionally substituted with one or more        substituents independently selected from the group consisting of        R⁹, OR⁹, NR¹⁰R¹¹, OH, Cl, and Br;    -   L¹ is absent, or is selected from the group consisting of C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, and C₁-C₆        alkylene-O—; wherein the L¹ C₁-C₆ alkylene, C₂-C₆ alkenylene,        and C₂-C₆ alkynylene, alone or as part of a group, are        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, OH, and oxo;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered        aryl, 5-11 membered heteroaryl, and 4-6 membered monocyclic        heterocycle fused to a phenyl group; wherein the R⁵ C₆-C₁₀        membered aryl, 5-11 membered heteroaryl, and 4-6 membered        monocyclic heterocycle fused to a phenyl group, are optionally        substituted with one or more substituents independently selected        from the group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, Br and        I;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆        alkyl is optionally substituted with one or more substituents        independently selected from the group consisting of R¹⁵, and F;        wherein the R⁶ 5-11 membered heteroaryl, and C₃-C₁₁ cycloalkyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R¹⁸ and        OR¹⁸;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 6-10 membered aryl, and C₃-C₁₁        cycloalkyl; wherein each R⁹ C₁-C₆ alkyl is optionally        substituted with one or more substituents independently selected        from the group consisting of CN, and F; wherein each R⁹ 6-10        membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl        is optionally substituted with one or more substituents        independently selected from the group consisting of R²⁴, OR²⁴,        and F;    -   R¹⁰ and R¹¹, at each occurrence, are each independently C₁-C₆        alkyl;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12        membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11        membered heteroaryl, and 4-12 membered heterocyclyl is        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆        alkyl)₂, oxo, CN, F, and C₁;    -   R¹³ and R¹⁴, at each occurrence, are each independently hydrogen        or C₁-C₆ alkyl;    -   R¹⁵, at each occurrence, is independently C₃-C₁₁ cycloalkyl;    -   R¹⁸, at each occurrence, is independently C₁-C₆ alkyl; wherein        each R¹⁸ C₁-C₆ alkyl is optionally substituted with one or more        F; and    -   R²⁴, at each occurrence, is independently C₁-C₆ alkyl.

In one embodiment of Formula (III),

-   -   R¹ is selected from the group consisting of C(O)R⁶, C(O)OR⁶, and        C(O)NR⁷R⁸;    -   R⁴ is selected from the group consisting of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ aryl and (C₁-C₆ alkylene)_(x)-5-11 membered        heteroaryl; wherein the R⁴ C₆-C₁₀ membered aryl of (C₁-C₆        alkylene)_(x)-C₆-C₁₀ membered aryl, and the 5-11 membered        heteroaryl of (C₁-C₆ alkylene)_(x)-5-11 membered heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        NR¹⁰R¹¹, OH, Cl, and Br;    -   R⁵ is selected from the group consisting of C₆-C₁₀ membered aryl        and 5-11 membered heteroaryl; wherein the R⁵ C₆-C₁₀ membered        aryl and 5-11 membered heteroaryl are optionally substituted        with one or more substituents independently selected from the        group consisting of R¹², OR¹², NR¹³R¹⁴, F, Cl, and Br;    -   R⁶ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;        wherein the R⁶ C₁-C₆ alkyl is optionally substituted with one or        more independently selected R¹⁵; wherein the R⁶ C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl are optionally        substituted with one or more independently selected OR¹⁸;    -   R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹        C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally        substituted with one or more F; wherein each R⁹ 6-10 membered        C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R²⁴, OR²⁴, and F;    -   R¹⁰ and R¹¹, at each occurrence, are each independently selected        C₁-C₆ alkyl;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, 6-10 membered        aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12        membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered        heterocyclyl is optionally substituted with one or more        independently selected from the group consisting of C₁-C₆ alkyl;    -   R¹³ and R¹⁴, at each occurrence, are each independently C₁-C₆        alkyl;    -   R¹⁵, at each occurrence, is independently selected C₃-C₁₁        cycloalkyl;    -   R¹⁸, at each occurrence, is independently selected C₁-C₆ alkyl;    -   R²⁴, at each occurrence, is independently selected C₁-C₆ alkyl;        and    -   x is 0 or 1.

Exemplary compounds of Formula (III) include, but are not limited to

-   (2S*,3R*,4S*,5S*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclohexyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluoro-4-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(4-fluoro-2-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2,4-difluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(4-methylphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(3-chiorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(piperidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoroazetidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoropyrrolidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(prop-2-en-1-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-cyclobutyl-5-methoxypyridin-4-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]phenyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(3,6-dihydro-2H-pyran-4-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-(oxane-4-carbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(oxane-4-carbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(oxane-4-carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-1-(ethoxycarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-[2-(difluoromethyl)phenyl]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2,6-difluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-([1,1′-biphenyl]-2-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-cyanopropan-2-yl)-2-methoxyphenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrazol-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[3′-(dimethylamino)[1,1′-biphenyl]-2-yl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2′-methyl[1,1′-biphenyl]-2-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyridin-4-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyrimidin-5-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(furan-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrrol-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[3′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-[2-(2H-1,3-benzodioxol-5-yl)phenyl]-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(6-methoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[4′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(4′-cyano[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-{2-[6-(trifluoromethyl)pyridin-3-yl]phenyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-[2-(5-ethoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-5-(1-benzofuran-7-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(2-methylpropyl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(6-methoxypyridine-2-sulfonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopropyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-7-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethoxy)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-3-methoxypyridin-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({[2-methoxy-5-(trifluoromethyl)pyridin-3-yl](²H₂)methyl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)pyridin-3-yl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)phenyl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[(5-tert-butyl-2-methoxyphenyl)(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-chloro-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-6,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-8-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({2-[2-methoxy-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxoethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-{[(1,1,1-trifluoropropan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2R)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-hydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-methoxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopropane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopentane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-4-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]propoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(5-iodo-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1R,2R)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1S,2S)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[(5-chloro-2-methoxypyridin-3-yl)oxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(²H₃)methylphenyl]-1-[(2S,3S)-(2,3-²H₂)oxane-2-carbonyl](2-²H)pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenoxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-4-[(5-bromo-1-benzofuran-2-yl)methoxy]-3-tert-butyl-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]-4-{[7-(trifluoromethyl)-1-benzofuran-2-yl]methoxy}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-1-benzofuran-2-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(naphthalene-1-sulfonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylic    acid;-   (2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-1-benzofuran-2-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylic    acid; and pharmaceutically acceptable salts thereof.

Compounds of the invention are named by using Name 2015 Pack 2 namingalgorithm by Advanced Chemical Development or Struct=Name namingalgorithm as part of CHEMDRAW® ULTRA v. 12.0.2.1076 or ProfessionalVersion 15.0.0.106.

Compounds of the invention may exist as stereoisomers wherein asymmetricor chiral centers are present. These stereoisomers are “R” or “S”depending on the configuration of substituents around the chiral carbonatom. The terms “R” and “S” used herein are configurations as defined inIUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates variousstereoisomers and mixtures thereof and these are specifically includedwithin the scope of this invention. Stereoisomers include enantiomersand diastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of compounds of the invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by methods of resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers by precipitation orchromatography and optional liberation of the optically pure productfrom the auxiliary as described in Furniss, Hannaford, Smith, andTatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition(1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2)direct separation of the mixture of optical enantiomers on chiralchromatographic columns or (3) fractional recrystallization methods.

Compounds of the invention may exist as cis or trans isomers, whereinsubstituents on a ring may attached in such a manner that they are onthe same side of the ring (cis) relative to each other, or on oppositesides of the ring relative to each other (trans). For example,cyclobutane may be present in the cis or trans configuration, and may bepresent as a single isomer or a mixture of the cis and trans isomers.Individual cis or trans isomers of compounds of the invention may beprepared synthetically from commercially available starting materialsusing selective organic transformations, or prepared in single isomericform by purification of mixtures of the cis and trans isomers. Suchmethods are well-known to those of ordinary skill in the art, and mayinclude separation of isomers by precipitation or chromatography.

It should be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention.

The present disclosure includes all pharmaceutically acceptableisotopically-labelled compounds of Formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature. Examples of isotopes suitable for inclusion inthe compounds of the disclosure include isotopes of hydrogen, such as ²Hand ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S. Certain isotopically-labelled compounds ofFormula (I) for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Substitution with heavierisotopes such as deuterium, i.e. ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements, and hencemay be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy. Isotopically-labeled compounds of Formula (I) maygenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples using an appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Compounds of Formula (I), (II), and (III) may be used in the form ofpharmaceutically acceptable salts. The phrase “pharmaceuticallyacceptable salt” means those salts which are, within the scope of soundmedical judgement, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse and the like and are commensurate with a reasonablebenefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge etal. J. Pharmaceutical Sciences, 1977, 66: 1-19.

Compounds of Formula (I), (II), and (III) may contain either a basic oran acidic functionality, or both, and can be converted to apharmaceutically acceptable salt, when desired, by using a suitable acidor base. The salts may be prepared in situ during the final isolationand purification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups may bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid, and citric acid.

Basic addition salts may be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Other examples oforganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, refers to derivatives of the compounds of the invention whichhave cleavable groups. Such derivatives become, by solvolysis or underphysiological conditions, the compounds of the invention which arepharmaceutically active in vivo. Prodrugs of the compounds of theinvention are, within the scope of sound medical judgement, suitable foruse in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The invention contemplates compounds of Formula (I), (II), and (III)formed by synthetic means or formed by in vivo biotransformation of aprodrug.

Compounds described herein may exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

Pharmaceutical Compositions

When employed as a pharmaceutical, a compound of the invention istypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise a therapeutically effective amount of acompound of Formula (I), (II), (III), or a pharmaceutically acceptablesalt thereof together with a pharmaceutically acceptable carrier. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type.

Methods of Use

The compounds and compositions using any amount and any route ofadministration may be administered to a subject for the treatment orprevention of cystic fibrosis, pancreatic insufficiency, Sjögren'ssyndrome (SS), chronic obstructive lung disease (COLD), or chronicobstructive airway disease (COAD).

The term “administering” refers to the method of contacting a compoundwith a subject. Thus, the compounds may be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, parentally, or intraperitoneally. Also,the compounds described herein may be administered by inhalation, forexample, intranasally. Additionally, the compounds may be administeredtransdermally, topically, and via implantation. In certain embodiments,the compounds and compositions thereof may be delivered orally. Thecompounds may also be delivered rectally, bucally, intravaginally,ocularly, or by insufflation. CFTR-modulated disorders and conditionsmay be treated prophylactically, acutely, and chronically usingcompounds and compositions thereof, depending on the nature of thedisorder or condition. Typically, the host or subject in each of thesemethods is human, although other mammals may also benefit from theadministration of compounds and compositions thereof as set forthhereinabove.

Compounds of the invention are useful as modulators of CFTR. Thus, thecompounds and compositions are particularly useful for treating orlessening the severity or progression of a disease, disorder, or acondition where hyperactivity or inactivity of CFTR is involved.Accordingly, the invention provides a method for treating cysticfibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronicobstructive lung disease (COLD), or chronic obstructive airway disease(COAD) in a subject, wherein the method comprises the step ofadministering to said subject a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a preferred embodiment thereof as set forth above, with or without apharmaceutically acceptable carrier. Particularly, the method is for thetreatment or prevention of cystic fibrosis. In a more particularembodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V,and/or VI mutation.

In a particular embodiment, the present invention provides compounds ofthe invention, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising a compound of the invention, foruse in medicine. In a particular embodiment, the present inventionprovides compounds of the invention, or a pharmaceutically acceptablesalt thereof, or pharmaceutical compositions comprising a compound ofthe invention, for use in the treatment of cystic fibrosis, pancreaticinsufficiency, Sjögren's syndrome (SS), chronic obstructive lung disease(COLD) or chronic obstructive airway disease (COAD). In a moreparticular embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the treatment of cystic fibrosis. In a moreparticular embodiment, the cystic fibrosis is caused by a Class I, II,III, IV, V, and/or VI mutation.

One embodiment is directed to the use of a compound according to Formula(I), (II), (III), or a pharmaceutically acceptable salt thereof in thepreparation of a medicament. The medicament optionally can comprise oneor more additional therapeutic agents. In some embodiments, themedicament is for use in the treatment of cystic fibrosis, pancreaticinsufficiency, Sjögren's syndrome (SS), chronic obstructive lung disease(COLD) or chronic obstructive airway disease (COAD). In a particularembodiment, the medicament is for use in the treatment of cysticfibrosis. In a more particular embodiment, the cystic fibrosis is causedby a Class I, II, III, IV, V, and/or VI mutation.

This invention also is directed to the use of a compound according toFormula (I), (II), (III), or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for the treatment of cystic fibrosis,Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lungdisease, and chronic obstructive airway disease. The medicamentoptionally can comprise one or more additional therapeutic agents. In aparticular embodiment, the invention is directed to the use of acompound according to Formula (I) II), (III), or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for thetreatment of cystic fibrosis. In a more particular embodiment, thecystic fibrosis is caused by a Class I, II, III, IV, V, and/or VImutation.

In one embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents. In another embodiment, the present inventionprovides pharmaceutical compositions comprising a compound of theinvention, or a pharmaceutically acceptable salt thereof, and one ormore additional therapeutic agents wherein the additional therapeuticagents are selected from the group consisting of CFTR modulators andCFTR amplifiers. In another embodiment, the present invention providespharmaceutical compositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents wherein the additional therapeutic agents are CFTRmodulators.

In one embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents. In one embodiment, the present invention providespharmaceutical compositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, one potentiator, and one ormore additional correctors. In one embodiment, the present inventionprovides pharmaceutical compositions comprising a compound of theinvention, and another therapeutic agent. In a particular embodiment,the other therapeutic agent is a cystic fibrosis treatment agent. In oneembodiment, the present invention provides a method for treating cysticfibrosis in a subject comprising administering a compound of theinvention, or a pharmaceutically acceptable salt thereof, and one ormore additional therapeutic agents. In another embodiment, the presentinvention provides a method for treating cystic fibrosis in a subjectcomprising administering a compound of the invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents wherein the additional therapeutic agents areselected from the group consisting of CFTR modulators and CFTRamplifiers. In one embodiment, the present invention provides a methodfor treating cystic fibrosis in a subject comprising administering acompound of the invention, or a pharmaceutically acceptable saltthereof, and one or more additional therapeutic agents wherein theadditional therapeutic agents are CFTR modulators. In one embodiment,the present invention provides a method for treating cystic fibrosis ina subject comprising administering a compound of the invention, or apharmaceutically acceptable salt thereof, and, and another therapeuticagent. In a particular embodiment, the other therapeutic agent is acystic fibrosis treatment agent. In one embodiment, the presentinvention provides a method for treating cystic fibrosis in a subjectcomprising administering a therapeutically effective amount of acompound of the invention, or a pharmaceutically acceptable saltthereof. In a particular embodiment, the additional therapeutic agent(s)are one potentiator, and one or more additional correctors. In anotherembodiment, the additional therapeutic agent(s) is selected from thegroup consisting of CFTR modulators and CFTR amplifiers. In anotherembodiment, the other therapeutic agent(s) is a CFTR modulator. In amore particular embodiment, the cystic fibrosis is caused by a Class I,II, III, IV, V, and/or VI mutation.

The present compounds or pharmaceutically acceptable salts thereof maybe administered as the sole active agent or it may be co-administeredwith other therapeutic agents, including other compounds orpharmaceutically acceptable salts thereof, that demonstrate the same ora similar therapeutic activity and that are determined to be safe andefficacious for such combined administration. The present compounds maybe co-administered to a subject. The term “co-administered” means theadministration of two or more different therapeutic agents to a subjectin a single pharmaceutical composition or in separate pharmaceuticalcompositions. Thus co-administration involves administration at the sametime of a single pharmaceutical composition comprising two or moretherapeutic agents or administration of two or more differentcompositions to the same subject at the same or different times.

The compounds of the invention or pharmaceutically acceptable saltsthereof may be co-administered with a therapeutically effective amountof one or more additional therapeutic agents to treat a CFTR mediateddisease, where examples of therapeutic agents include, but are notlimited to antibiotics (for example, aminoglycosides, colistin,aztreonam, ciprofloxacin, and azithromycin), expectorants (for example,hypertonic saline, acetylcysteine, dornase alfa, and denufosol),pancreatic enzyme supplements (for example, pancreatin, andpancrelipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTRmodulators (for example, CFTR potentiators, CFTR correctors), and CFTRamplifiers. In one embodiment, the CFTR mediated disease is cysticfibrosis, chronic obstructive pulmonary disease (COPD), dry eye disease,pancreatic insufficiency, or Sjögren's syndrome. In one embodiment, theCFTR mediated disease is cystic fibrosis.

In one embodiment, the compounds of the invention or pharmaceuticallyacceptable salts thereof may be co-administered with one or two CFTRmodulators and one CFTR amplifier. In one embodiment, the compounds ofthe invention or pharmaceutically acceptable salts thereof may beco-administered with one potentiator, one or more correctors, and oneCFTR amplifier. In one embodiment, the compounds of the invention orpharmaceutically acceptable salts thereof may be co-administered withone or more CFTR modulators. In one embodiment, the compounds of theinvention or pharmaceutically acceptable salts thereof may beco-administered with one CFTR modulators. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered with two CFTR modulators. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered with three CFTR modulators. In one embodiment,the compounds of the invention or pharmaceutically acceptable saltsthereof may be co-administered with one potentiator and one or morecorrectors. In one embodiment, the compounds of the invention orpharmaceutically acceptable salts thereof may be co-administered withone potentiator and two correctors. In one embodiment, the compounds ofthe invention or pharmaceutically acceptable salts thereof may beco-administered with one potentiator. In one embodiment, the compoundsof the invention or pharmaceutically acceptable salts thereof may beco-administered with one or more correctors. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered with one corrector. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered with two correctors.

Examples of CFTR potentiators include, but are not limited to, Ivacaftor(VX-770), CTP-656, NVS-QBW251, FD1860293, GLPG2451, GLPG3067, GLPG1837,PTI-808,N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide,and3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.Examples of potentiators are also disclosed in publications:WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421,WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378,WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823,WO2014/180562, WO2015018823, WO 2016193812 and U.S. application Ser. No.15/502,892.

In one embodiment, the potentiator can be selected from the groupconsisting of

-   Ivacaftor (VX-770,    N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide);-   GLPG1837;-   GLP-2451;-   PTI-808;-   CTP-656;-   NVS-QBW251;-   GLPG3067;-   FD1860293;-   2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide;-   2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide-   2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide;-   5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-ethyl-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide;-   2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;-   4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-3-carboxamide;-   2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;-   2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;-   5-(2-methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid    (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-methoxypropyl)-1H-pyrazole-3-carboxamide;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-1H-pyrazole-3-carboxamide;-   2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;-   2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;-   2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;-   [5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl    dihydrogen phosphate;-   [3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl    dihydrogen phosphate;-   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dioxan-2-yl)-1H-pyrazole-3-carboxamide;-   5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide;-   2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;-   3-amino-N-(2-hydroxy-2-methylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;-   3-amino-N-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;-   3-amino-N-(3-hydroxy-2,2-dimethylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;-   3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide;-   3-amino-5-[(4-fluorophenyl)    sulfonyl]-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]pyridine-2-carboxamide;-   3-amino-5-[(3-fluorophenyl)    sulfonyl]-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide;-   3-amino-N-[2-(cyclopropylamino)-2-oxoethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;-   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(azetidin-1-yl)methanone;-   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-(hydroxymethyl)azetidin-1-yl]methanone;-   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroazetidin-1-yl)methanone;-   3-amino-N-[(2R)-2-hydroxy-3-methoxypropyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;-   (3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone;-   (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone;-   rac-3-amino-N-[(3R,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;-   3-amino-5-[(4,4-difluoropiperidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;-   (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;-   3-amino-N-(2-hydroxy-4-methylpentyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;-   (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)    (3-hydroxy-3-methylazetidin-1-yl)methanone;-   3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-{[4-(trifluoromethyl)piperidin-1-yl]sulfonyl}pyridine-2-carboxamide;-   3-amino-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;-   3-amino-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide;-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2R)-2-hydroxy-3-methoxypropyl]pyridine-2-carboxamide;-   3-amino-N-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;-   (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3R)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;-   (3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;-   3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;-   3-amino-N-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;-   3-amino-N-(3-tert-butoxy-2-hydroxypropyl)-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;-   [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;-   {3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;    and-   3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.

Non-limiting examples of correctors include Lumacaftor (VX-809),1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide(VX-661), VX-983, GLPG2851, GLPG2222, GLPG2665, GLPG2737, GLPG3221,PTI-801, VX-152, VX-440, VX-445, VX-659, FDL169, FDL304, FD2052160, andFD2035659. Examples of correctors are also disclosed in U.S. applicationSer. Nos. 14/925,649, 14/926,727, 15/205,512, 15/287,922, 15/287,911,15/287,922, 15/287,911, and 15/492,094.

In one embodiment, the corrector(s) can be selected from the groupconsisting of Lumacaftor (VX-809);

-   1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide    (VX-661);-   PTI-801;-   VX-983;-   GLPG2665;-   GLPG2851;-   GLPG2222;-   VX-152;-   VX-440;-   VX-659;-   VX-445;-   FDL169-   FDL304;-   FD2052160;-   FD2035659;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyclopentanecarboxylic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]benzamide;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic    acid;-   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic    acid;-   4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic    acid;-   3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic    acid;-   5-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]pyrazine-2-carboxylic    acid;-   6-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic    acid;-   trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   6-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic    acid;-   trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   ethyl    trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;-   cis-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclopropane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid; and-   trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid.

In one embodiment, the additional therapeutic agent is a CFTR amplifier.CFTR amplifiers enhance the effect of known CFTR modulators, such aspotentiators and correctors. Examples of CFTR amplifiers are PTI130 andPTI-428. Examples of amplifiers are also disclosed in publications:WO2015138909 and WO2015138934.

In one embodiment, the additional therapeutic agent is a CFTRstabilizer. CFTR stabilizers enhance the stability of corrected CFTRthat has been treated with a corrector, corrector/potentiator or otherCFTR modulator combination(s). An example of a CFTR stabilizer iscavosonstat (N91115). Examples of stabilizers are also disclosed inpublication: WO2012048181.

In one embodiment, the additional therapeutic agent is an agent thatreduces the activity of the epithelial sodium channel blocker (ENaC)either directly by blocking the channel or indirectly by modulation ofproteases that lead to an increase in ENaC activity (e.g., serineproteases, channel-activating proteases). Exemplary of such agentsinclude camostat (a trypsin-like protease inhibitor), QAU145, 552-02,GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agentsthat reduce the activity of the epithelial sodium channel blocker (ENaC)can be found, for example, in PCT Publication No. WO2009074575 andWO2013043720; and U.S. Pat. No. 8,999,976.

In one embodiment, the ENaC inhibitor is VX-371.

In one embodiment, the ENaC inhibitor is SPX-101 (S18).

In one embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents. In a particular embodiment, the additionaltherapeutic agents are selected from the group consisting of CFTRmodulators and CFTR amplifiers. In a further embodiment, the additionaltherapeutic agents are CFTR modulators. In one embodiment, the presentinvention provides pharmaceutical compositions comprising a compound ofthe invention, or a pharmaceutically acceptable salt thereof, onepotentiator, and one or more additional correctors.

This invention also is directed to kits that comprise one or morecompounds and/or salts of the invention, and, optionally, one or moreadditional therapeutic agents.

This invention also is directed to methods of use of the compounds,salts, compositions, and/or kits of the invention to, with or withoutone or more additional therapeutic agents, for example, modulate theCystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, andtreat a disease treatable by modulating the Cystic FibrosisTransmembrane Conductance Regulator (CFTR) protein (including cysticfibrosis, Sjögren's syndrome, pancreatic insufficiency, chronicobstructive lung disease, and chronic obstructive airway disease).

Chemical Synthetic Procedures General

The compounds of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e. reaction temperatures, times, mole ratios of reactants,solvents, pressures, etc.) were given, other process conditions can alsobe used unless otherwise stated. Optimum reaction conditions may varywith the particular reactants or solvent used, but such conditions canbe determined by one skilled in the art by routine optimizationprocedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art (Protective Groups in Organic Synthesis Third Edition; Greene, TW and Wuts, P G M, Eds.; Wiley-Interscience: New York, 1991).

The following methods are presented with details as to the preparationof a compound of the invention as defined hereinabove and thecomparative examples. A compound of the invention may be prepared fromknown or commercially available starting materials and reagents by oneskilled in the art of organic synthesis.

All reagents were of commercial grade and were used as received withoutfurther purification, unless otherwise stated. Commercially availableanhydrous solvents were used for reactions conducted under inertatmosphere. Reagent grade solvents were used in all other cases, unlessotherwise specified. Column chromatography was performed on silica gel60 (35-70 μm). Thin layer chromatography was carried out usingpre-coated silica gel F-254 plates (thickness 0.25 mm). ¹H NMR spectrawere recorded on a Bruker Advance 300 NMR spectrometer (300 MHz), anAgilent 400 MHz NMR spectrometer or a 500 MHz spectrometer. Chemicalshifts (δ ppm) for ¹H NMR spectra were reported in parts per million(ppm) relative to tetramethylsilane (δ ppm 0.00) or the appropriateresidual solvent peak, i.e. CHCl₃ (δ ppm 7.27), as internal reference.Multiplicities were given as singlet (s), doublet (d), doublet ofdoublets of doublets (ddd), doublet of doublets of doublets of doublets(dddd), doublet of doublets of quartets (ddq), doublet of doublets oftriplets (ddt), doublet of quartets (dq), doublet of triplets ofdoublets (dtd), heptet (hept), triplet (t), triplet of doublets ofdoublets (tdd), triplet of quartets (tq), quartet (q), quartet ofdoublets (qd), quartet of triplets (qt), quintuplet (quin), multiplet(m) and broad (br). Electrospray MS spectra were obtained on a Watersplatform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupledto a Waters Mass detector 3100 spectrometer. Columns used: WatersAcquity UPLC BEH C18 1.7 μm, 2.1 mm ID×50 mm L, Waters Acquity UPLC BEHC18 1.7 μm, 2.1 mm ID×30 mm L, or Waters Xterra® MS 5 μm C18, 100×4.6mm. The methods were using either MeCN/H₂O gradients (H₂O containseither 0.1% TFA or 0.1% NH₃) or MeOH/H₂O gradients (H₂O contains 0.05%TFA). Microwave heating was performed with a Biotage® Initiator.

Racemic mixtures were separated on an Agilent HP1100 system with UVdetection. Column used: Chiralpak® IA (10×250 mm, 5 μm). Solvents used:iPrOH and tBME. Enantiomeric purity was determined on an Agilent HP1100system with UV detection. Column used: Chiralpak® IA (4.6×250 mm, 5 μm).Solvents used: iPrOH and tBME.

Reverse Phase Purification Methods Prep LC/MS Method TFA6

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 40 mL/minute (0-0.5 min 15% A, 0.5-8.0 min lineargradient 15-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 minlinear gradient 100-15% A, 9.1-10 min 15% A). A custom purificationsystem was used, consisting of the following modules: Gilson 305 and 306pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson506C interface box; Gilson FC204 fraction collector; Agilent G1968DActive Splitter; Thermo MSQ Plus mass spectrometer. The system wascontrolled through a combination of Thermo Xcalibur 2.0.7 software and acustom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method TFA7

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å™ AXIA column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 40 mL/minute (0-0.5 min 25% A, 0.5-8.0 min lineargradient 25-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 minlinear gradient 100-25% A, 9.1-10 min 25% A). A custom purificationsystem was used, consisting of the following modules: Gilson 305 and 306pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson506C interface box; Gilson FC204 fraction collector; Agilent G1968DActive Splitter; Thermo MSQ Plus mass spectrometer. The system wascontrolled through a combination of Thermo Xcalibur 2.0.7 software and acustom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method TFA8

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 40 mL/minute (0-0.5 min 35% A, 0.5-8.0 min lineargradient 35-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 minlinear gradient 100-35% A, 9.1-10 min 35% A). A custom purificationsystem was used, consisting of the following modules: Gilson 305 and 306pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson506C interface box; Gilson FC204 fraction collector; Agilent G1968DActive Splitter; Thermo MSQ Plus mass spectrometer. The system wascontrolled through a combination of Thermo Xcalibur 2.0.7 software and acustom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method TFA10

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 30 mL/minute (0-0.2 min 5% A, 0.2-3.0 min linear gradient5-100% A, 4.1-4.5 min 100-5% A, 4.5-5.0 min 5% A). A custom purificationsystem was used, consisting of the following modules: Gilson 305 and 306pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson506C interface box; Gilson FC204 fraction collector; Agilent G1968DActive Splitter; Thermo MSQ Plus mass spectrometer. The system wascontrolled through a combination of Thermo Xcalibur 2.0.7 software and acustom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method AA6

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at aflow rate of 40 mL/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient15-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min lineargradient 100-15% A, 9.1-10 min 15% A). A custom purification system wasused, consisting of the following modules: Gilson 305 and 306 pumps;Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506Cinterface box; Gilson FC204 fraction collector; Agilent G1968D ActiveSplitter; Thermo MSQ Plus mass spectrometer. The system was controlledthrough a combination of Thermo Xcalibur 2.0.7 software and a customapplication written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method AA7

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ (50 mm×21.2 mm). A gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of40 mL/minute (0-0.5 min 25% A, 0.5-8.0 min linear gradient 25-100% A,8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient100-25% A, 9.1-10 min 25% A). A custom purification system was used,consisting of the following modules: Gilson 305 and 306 pumps; Gilson806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interfacebox; Gilson FC204 fraction collector; Agilent G1968D Active Splitter;Thermo MSQ Plus mass spectrometer. The system was controlled through acombination of Thermo Xcalibur 2.0.7 software and a custom applicationwritten in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method AA8

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at aflow rate of 40 mL/minute (0-0.5 min 35% A, 0.5-8.0 min linear gradient35-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min lineargradient 100-35% A, 9.1-10 min 35% A). A custom purification system wasused, consisting of the following modules: Gilson 305 and 306 pumps;Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506Cinterface box; Gilson FC204 fraction collector; Agilent G1968D ActiveSplitter; Thermo MSQ Plus mass spectrometer. The system was controlledthrough a combination of Thermo Xcalibur 2.0.7 software and a customapplication written in-house using Microsoft Visual Basic 6.0.

Stereochemistry of final compounds was arbitrarily assigned in somecases, based on the order of elution and/or activity with respect toexisting analogs.

List of abbreviations that may be used in the experimental section:

Abbreviation Definition MeCN acetonitrile eq equivalents TFAtrifluoroacetic acid NMR nuclear magnetic resonance DMSO dimethylsulfoxide LC/MS or LCMS liquid chromatography-mass spectrometry MeOHmethanol tBME tert-butyl methyl ether s singlet br s broad singlet dduplet or doublet dd double duplet or doublet of doublets m multipletmin minute mL or mL milliliter μL microliter g gram mg milligram mmolmillimoles HPLC high pressure liquid chromatography ppm parts permillion Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene μmmicrometer iPrOH iso-propanol DBU 1,8-diazabicycloundec-7-ene HATU1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate EDC or EDCIN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide

Synthetic Preparation of the Compounds of the Invention Schemes

The compounds of the present disclosure can be better understood inconnection with the following synthetic schemes and methods whichillustrate a means by which the compounds can be prepared. The compoundsof this disclosure can be prepared by a variety of synthetic procedures.Representative procedures are shown in, but are not limited to, Schemes1-7.

As shown in Scheme 1, core compounds of formula (2) can be prepared fromcompounds of formula (1). Compounds of formula (1), wherein R^(A) istypically C₁-C₆ alkyl and R⁵ is as described herein, can be treatedfirst with lithium bromide, followed by(E)-3,3-dimethyl-1-nitrobut-1-ene in the presence of a base such as, butnot limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, orpotassium carbonate in a solvent such as but not limited to toluene, ortetrahydrofuran to provide a racemic mixture of compounds of formula(2). The reaction is typically performed at a reduced temperature, suchas −78° C., before quenching with aqueous saturated ammonium chloride.

Alternatively, a mixture of compounds of formula (1) and(E)-3,3-dimethyl-1-nitrobut-1-ene, wherein R^(A) is typically C₁-C₆alkyl and R⁵ is as described herein, can be treated withacetyl(oxo)silver in the presence of molecular sieves and a base suchas, but not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene,triethylamine, or potassium carbonate in a solvent such as but notlimited to toluene or tetrahydrofuran to provide a racemic mixture ofcore compounds of formula (2). The reaction is typically performed in anice bath before warming to room temperature and quenching with aqueoussaturated aqueous ammonium chloride.

As shown in Scheme 2, core compounds of formula (3) and (4) can beprepared from compounds of formula (1). Compounds of formula (1),wherein R^(A) is typically C₁-C₆ alkyl and R⁵ is as described herein,can be added to a prepared mixture of(2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)ironand copper (I) triflate dimer in a solvent such as, but not limited to,tetrahydrofuran, under an inert gas such as but not limited to argon ornitrogen, followed by the addition of (E)-3,3-dimethyl-1-nitrobut-1-ene,and a base such as, but not limited to potassium tert-butoxide, toprovide core compounds of formula (3) and (4). The reaction is typicallyperformed at reduced temperature, such as but not limited to 0° C. Corecompounds (3) and (4) may be obtained as a mixture or may be separatedby precipitation or chromatography. Core compound (3) is typically themajor isomer.

As shown in Scheme 3, compounds of formula (12) can be prepared fromcompounds of formula (3).

Carboxylic acids of formula (5) can be coupled with amine cores offormula (3) to provide compounds of formula (7). Examples of conditionsknown to generate compounds of formula (7) from a mixture of acarboxylic acid and an amine include, but are not limited to, adding acoupling reagent such as, but not limited to,N-(3-dimethylaminopropyl)-N-ethylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or thecorresponding hydrochloride salt, 1,3-dicyclohexylcarbodiimide (DCC),bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide or2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate or1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HBTU), and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®).The coupling reagents may be added as a solid, a solution, or as thereagent bound to a solid support resin. In addition to the couplingreagents, auxiliary-coupling reagents may facilitate the couplingreaction. Auxiliary coupling reagents that are often used in thecoupling reactions include but are not limited to4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT)and 1-hydroxybenzotriazole (HOBT). The reaction may be carried outoptionally in the presence of a base such as, but not limited to,triethylamine, N,N-diisopropylethylamine or pyridine. The couplingreaction may be carried out in solvents such as, but not limited to,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, and ethyl acetate. The reactions may becarried out at ambient temperature or heated. The heating can beaccomplished either conventionally or with microwave irradiation.

Alternatively, carboxylic acids of formula (5) can be converted to thecorresponding acid chlorides of formula (6) by reaction with thionylchloride, PCl₃, PCl₅, cyanuric chloride, or oxalyl chloride. Thereactions with thionyl chloride and oxalyl chloride can be catalyzedwith N,N-dimethylformamide at ambient temperature in a solvent such asdichloromethane. The resultant acid chlorides of formula (6) (orcommercially available acid chlorides of formula (6)) can then reactedwith core amines of formula (3) optionally in the presence of a basesuch as a tertiary amine base such as but not limited to triethylamineor N,N-diisopropylethylamine or an aromatic base such as pyridine, atroom temperature or heated in a solvent such as dichloromethane toprovide compounds of formula (7).

Compounds of formula (7) can be reacted with a freshly prepared solutionof chromium (II) chloride at to provide compounds of formula (8). Thereaction is typically performed under nitrogen at an elevatedtemperature such as reflux, in a solvent such as, but not limited to,ethanol. Remaining hydrolyzed acid, if any, can be converted back to theester using esterification conditions known in the art and literaturesuch as acetyl chloride in refluxing ethanol. Compounds of formula (9)can be prepared from compounds of formula (8) by treating the latterwith a reducing agent such as, but not limited to, sodium borohydride.The reaction is typically performed at a reduced temperature such as 0°C. or below, in a solvent such as, but not limited to, ethanol, methanoland the like. Alcohols of formula (9) can be treated with a base suchas, but not limited to, sodium hydride, potassium carbonate, orpotassium tert-butoxide and compounds of formula (10), wherein R^(4A) isthe ring of R⁴ as described herein, to provide compounds of formula(11). The addition may be performed at reduced temperature, such as 0°C., before warming up to ambient or elevated temperature in a solventsuch as, but not limited to, dimethylformamide, tetrahydrofuran, and thelike. Esters of formula (10) can be hydrolyzed in an aqueous hydroxidesolution to provide acids of formula (12) which are representative ofFormula (I). The reaction is typically performed in a solvent such asbut not limited to methanol, tetrahydrofuran, or mixtures thereof, andmay be performed at ambient temperature or an elevated temperature.

As shown in Scheme 4, compounds of formula (12), which arerepresentative of compounds of Formula (I), can be prepared fromcompounds of formula (4). Compounds of formula (4) in saturated aqueousNaHCO₃ and a solvent such as, but not limited to, toluene, can betreated with allyl carbonochloridate to provide compounds of formula(14). The reaction is typically performed at ambient temperature.Compounds of formula (14) can be reacted with a freshly preparedsolution of chromium (II) chloride at to provide compounds of formula(15). The reaction is typically performed under nitrogen at an elevatedtemperature such as reflux in a solvent such as, but not limited to,ethanol. Remaining hydrolyzed acid, if any, can be converted back to theester using esterification conditions known in the art and literaturesuch as acetyl chloride in refluxing ethanol. Compounds of formula (16)can be prepared from compounds of formula (15) by treating the latterwith a reducing agent such as, but not limited to, sodium borohydride.The reaction is typically performed at a reduced temperature such as 0°C. or below, in a solvent such as but not limited to ethanol, methanoland the like. Alcohols of formula (16) can be treated with a base suchas, but not limited to, sodium hydride, potassium carbonate, orpotassium tert-butoxide and compounds of formula (10) wherein R^(4A) isthe ring of R⁴ as described herein, to provide compounds of formula(17). The addition may be performed at reduced temperature, such as 0°C., before warming up to ambient or elevated temperature in a solventsuch as, but not limited to, N,N-dimethylformamide, tetrahydrofuran, andthe like. Removal of the allyl carbamate protecting group in compoundsof formula (17) to provide compounds of formula (18) can be accomplishedby reacting the former with a palladium catalyst such as, but notlimited to, tetrakis(triphenylphosphine)palladium(0) in the presence of1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione. The reaction is typicallyperformed at ambient temperature in a solvent such as, but not limitedto, dichloromethane, ethyl acetate, acetonitrile, water or mixturesthereof.

Carboxylic acids of formula (5) can be coupled with amine cores offormula (18) to provide compounds of formula (11). Examples ofconditions known to generate compounds of formula (11) from a mixture ofa carboxylic acid and an amine include, but are not limited to, adding acoupling reagent such as, but not limited to,N-(3-dimethylaminopropyl)-N-ethylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or thecorresponding hydrochloride salt, 1,3-dicyclohexylcarbodiimide (DCC),bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide or2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate or1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HBTU), and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®).The coupling reagents may be added as a solid, a solution, or as thereagent bound to a solid support resin. In addition to the couplingreagents, auxiliary-coupling reagents may facilitate the couplingreaction. Auxiliary coupling reagents that are often used in thecoupling reactions include but are not limited to4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT)and 1-hydroxybenzotriazole (HOBT). The reaction may be carried outoptionally in the presence of a base such as, but not limited to,triethylamine, N,N-diisopropylethylamine or pyridine. The couplingreaction may be carried out in solvents such as, but not limited to,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, and ethyl acetate. The reactions may becarried out at ambient temperature or heated. The heating can beaccomplished either conventionally or with microwave irradiation.

Alternatively, carboxylic acids of formula (5) can be converted to thecorresponding acid chlorides of formula (6) by reaction with thionylchloride, PCl₃, PCl₅, cyanuric chloride, or oxalyl chloride. Thereactions with thionyl chloride and oxalyl chloride can be catalyzedwith N,N-dimethylformamide at ambient temperature in a solvent such asdichloromethane. The resultant acid chlorides of formula (6) (orcommercially available acid chlorides of formula (6)) can then reactedwith core amines of formula (18) optionally in the presence of a basesuch as a tertiary amine base such as but not limited to triethylamineor N,N-diisopropylethylamine or an aromatic base such as pyridine, atroom temperature or heated in a solvent such as dichloromethane toprovide compounds of formula (11).

Esters of formula (11) can be hydrolyzed in an aqueous hydroxidesolution to provide compounds of formula (12) which are representativeof Formula (I). The reaction is typically performed in a solvent suchas, but not limited to, methanol, tetrahydrofuran, or mixtures thereof,and may be performed at ambient temperature or an elevated temperature.

An alternative sequence for the preparation of compounds of Formula (12)is shown in Scheme 5. Removal of the allyl carbamate protecting group incompounds of formula (16) to provide compounds of formula (19) can beaccomplished by reacting the former with a palladium catalyst such as,but not limited to, tetrakis(triphenylphosphine)palladium(0) in thepresence of 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione. The reactionis typically performed at ambient temperature in a solvent such as, butnot limited to, dichloromethane, ethyl acetate, acetonitrile, water ormixtures thereof.

Carboxylic acids of formula (5) can be coupled with amine cores offormula (19) to provide compounds of formula (20). Examples ofconditions known to generate compounds of formula (20) from a mixture ofa carboxylic acid and an amine include, but are not limited to, adding acoupling reagent such as, but not limited to,1-chloro-N,N,2-trimethylprop-1-en-1-amine (Ghosez reagent),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or thecorresponding hydrochloride salt, 1,3-dicyclohexylcarbodiimide (DCC),bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide,2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HBTU), or2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®).The coupling reagents may be added as a solid, a solution, or as thereagent bound to a solid support resin. In addition to the couplingreagents, auxiliary-coupling reagents may facilitate the couplingreaction. Auxiliary coupling reagents that are often used in thecoupling reactions include but are not limited to4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT)and 1-hydroxybenzotriazole (HOBT). The reaction may be carried outoptionally in the presence of a base such as, but not limited to,triethylamine, N,N-diisopropylethylamine or pyridine. The couplingreaction may be carried out in solvents such as, but not limited to,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, and ethyl acetate. The reactions may becarried out at ambient temperature or heated. The heating can beaccomplished either conventionally or with microwave irradiation.

Alternatively, carboxylic acids of formula (5) can be converted to thecorresponding acid chlorides of formula (6) by reaction with thionylchloride, PCl₃, PCl₅, cyanuric chloride, or oxalyl chloride. Thereactions with thionyl chloride and oxalyl chloride can be catalyzedwith N,N-dimethylformamide at ambient temperature in a solvent such asdichloromethane. The resultant acid chlorides of formula (6) (orcommercially available acid chlorides of formula (6)) can then reactedwith core amines of formula (19) optionally in the presence of a basesuch as a tertiary amine base such as, but not limited to, triethylamineor N,N-diisopropylethylamine or an aromatic base such as pyridine, atroom temperature or heated in a solvent such as dichloromethane toprovide compounds of formula (20).

Compounds of formula (20) can be treated with a base such as, but notlimited to, sodium hydride, potassium carbonate, or potassiumtert-butoxide and compounds of formula (10) wherein R^(4A) is the ringof R⁴ as described herein to provide compounds of formula (11). Theaddition may be performed at reduced temperature, such as 0° C., beforewarming up to ambient or elevated temperature in a solvent such as, butnot limited to, dimethylformamide, tetrahydrofuran, and the like. Estersof formula (11) can be hydrolyzed in an aqueous hydroxide solution toprovide compounds of formula (12) which are representative of formula(I). The reaction is typically performed in a solvent such as, but notlimited to, methanol, tetrahydrofuran, or mixtures thereof, and may beperformed at ambient temperature or an elevated temperature.

Scheme 6 depicts examples of ways to diversify the substituents on anaromatic ring of the R⁴ group. Compounds of formula (25), wherein X isI, Br, Cl or triflate and Ar is aryl or heteroaryl, can be prepared asdescribed in Schemes 3, 4, or 5.

Compounds of formula (27) can be prepared by reacting compounds offormula (25) wherein X is I, Br, Cl or triflate with boronic acidcompounds of formula (26), wherein R⁹ is as described herein (or theboronic ester equivalents), under Suzuki coupling conditions known tothose skilled in the art and widely available in the literature. Thereaction typically requires the use of a base and a catalyst. Examplesof bases include, but are not limited to, potassium carbonate, potassiumt-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride.Examples of catalysts include, but are not limited to,tetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, bis(triphenylphosphine)palladium(II) dichloride, andtris(dibenzylideneacetone)dipalladium(0). The reaction may be conductedin a solvent such as, but not limited to, water, dioxane,1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,tetrahydrofuran and the like or mixtures thereof. The reaction may beconducted at ambient or elevated temperatures, and optionally in amicrowave oven. Esters of formula (27) can be hydrolyzed in an aqueoushydroxide solution to provide compounds of formula (28) which arerepresentative of formula (I). The reaction is typically performed in asolvent such as, but not limited to, methanol, tetrahydrofuran, ormixtures thereof, and may be performed at ambient temperature or anelevated temperature.

Compounds of formula (27) can be prepared by reacting compounds offormula (25) wherein X is I, Br, Cl or triflate with organozinccompounds of formula (29), wherein R⁹ is as described herein, underNegishi coupling conditions known to those skilled in the art and widelyavailable in the literature. The reaction typically requires the use ofa palladium or nickel catalyst. Examples of catalysts include, but arenot limited to,dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl), tetrakis(triphenylphosphine)nickel(0),tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, tris(dibenzylideneacetone)dipalladium(0), andpalladium(II) acetate. The reaction may be conducted in a solvent suchas, but not limited to, water, dioxane, 1-methyl-2-pyrrolidinone,N,N-dimethylacetamide, 1,2-dimethoxyethane, N,N-dimethylformamide,toluene, ethanol, tetrahydrofuran and the like, or mixtures thereof. Thereaction may be conducted at ambient or elevated temperatures, andoptionally in a microwave oven. Esters of formula (27) can be hydrolyzedin an aqueous hydroxide solution to provide compounds of formula (28)which are representative of Formula (I). The reaction is typicallyperformed in a solvent such as, but not limited to, methanol,tetrahydrofuran, or mixtures thereof, and may be performed at ambienttemperature or an elevated temperature.

Compounds of formula (31) can be prepared by reacting compounds offormula (25) wherein X is I, Br, Cl or triflate with amines compounds offormula (30), wherein R⁹ is H or is as described herein, underBuchwald-Hartwig amination conditions known to those skilled in the artand widely available in the literature. The reaction typically requiresthe use of a base, catalyst, and optionally, a ligand. Examples of basesinclude, but are not limited to, potassium carbonate, potassiumt-butoxide, sodium t-butoxide, sodium carbonate, cesium carbonate, andcesium fluoride. Examples of catalysts include, but are not limited to,dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl),chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct(RuPhos palladacycle), tetrakis(triphenylphosphine)nickel(0),tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, tris(dibenzylideneacetone)dipalladium(0), andpalladium(II) acetate. Examples of optional ligands include, but are notlimited to, BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl), DPPF(1,1′-bis(diphenylphosphino)ferrocene), and Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). The reaction may beconducted in a solvent such as, but not limited to, water, dioxane,1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, dimethoxyethane,N,N-dimethylformamide, toluene, ethanol, tetrahydrofuran, and the likeor mixtures thereof. The reaction may be conducted at ambient orelevated temperatures, and optionally in a microwave oven. Esters offormula (31) can be hydrolyzed in an aqueous hydroxide solution toprovide compounds of formula (32) which are representative of Formula(I). The reaction is typically performed in a solvent such as, but notlimited to, methanol, tetrahydrofuran, or mixtures thereof, and may beperformed at ambient temperature or an elevated temperature.

As shown in Scheme 7, compounds of formula (34), which arerepresentative of compounds of Formula (I), can be prepared fromcompounds of formula (12). Compounds of formula (12) can be reacted withcompounds of formula (33) in the presence of a coupling agent such as,but not limited to, carbonyldiimidazole and a base such as, but notlimited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction istypically performed at an elevated temperature in a solvent such as, butnot limited to, dichloromethane, dichloroethane, or the like.

EXAMPLES Catalyst and Intermediate Synthesis Catalyst 1(2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron

-he procedure for preparation of the chiral ligand was modified fromYan, X.-X., Peng, Q., Zhang, Y., Zhang, K., Hong, W., Hou, X.-L. and Wu,Y.-D., Angew. Chem., Int. Ed. 2006, 45 1979-1983.

Cyclopenta-2,4-dien-1-yl(3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)iron(515 mg, 1.733 mmol) was dissolved in 2-methyltetrahydrofuran (17 mL).The resulting solution was cooled to −78° C. in an acetone-dry ice bath,and tetramethylethylenediamine (0.340 mL, 2.253 mmol) was added,followed by dropwise addition of sec-butyllithium (1.485 mL, 2.080mmol), maintaining an internal temperature<−70° C. After stirring for 30minutes, the reaction mixture was treated withbis(3,5-bis(trifluoromethyl)phenyl)chlorophosphine (1110 mg, 2.253 mmol)in one portion. After stirring at −78° C. for 1 hour, the reaction flaskwas removed from the bath and warmed to ambient temperature beforediluting with 20 mL of methyl tert-butyl ether and quenching with 10 mLof saturated aqueous ammonium chloride. The layers were separated, andthe organic layer was washed with 10 mL of saturated ammonium chlorideand 10 mL of brine, dried over sodium sulfate, filtered andconcentrated. The crude material was purified via chromatography,eluting with isocratic 93:7 heptanes:methyl tert-butyl ether on an 80 gsilica gel column for 20 minutes to provide 920 mg of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.86 (d, J=6.6 Hz, 3H), 0.92 (d,J=6.3 Hz, 3H), 1.69-1.77 (m, 1H), 3.49-3.50 (m, 1H), 3.73-3.81 (m, 1H),3.96 (t, J=7.8 Hz, 1H), 4.21-4.27 (m, 6H), 4.46-4.48 (m, 1H), 5.00-5.01(m, 1H), 7.65 (d, J=6.3 Hz, 2H), 7.80 (s, 1H), 7.89 (d, J=6.0 Hz, 2H),7.93 (s, 1H); MS(ESI+) m/z 754.0 (M+H)⁺.

Intermediate 1 (E)-3,3-dimethyl-1-nitrobut-1-ene Intermediate 1A3,3-dimethyl-1-nitrobutan-2-ol

To a slurry of lithium aluminum hydride (0.881 g, 23.22 mmol) in drytetrahydrofuran (140 mL), which had been stirred for 30 minutes at 0°C., nitromethane (70.9 g, 1161 mmol) was added dropwise. After 30minutes, pivalaldehyde (20 g, 232 mmol) was added dropwise. The mixturewas stirred at 0° C. for 5 hours, and was quenched with 1N aqueous HCl.The reaction mixture was poured into water, extracted with CH₂Cl₂ (2×250mL), washed with brine (2×200 mL), dried over Na₂SO₄, filtered, andconcentrated to provide the title compound (17 g, 107 mmol, 46.3%yield). LC-MS (ESI⁻) m/z 146.7 (M−H)⁻.

Intermediate 1B (E)-3,3-dimethyl-1-nitrobut-1-ene

A solution of 3,3-dimethyl-1-nitrobutan-2-ol (10 g, 67.9 mmol) indichloromethane (100 mL) was cooled to −10° C. under N₂, treated with2,2,2-trifluoroacetic anhydride (15.70 g, 74.7 mmol), stirred at −15° C.for 5 minutes, treated dropwise with triethylamine (20.84 mL, 149 mmol)keeping the bath at −15° C. during the addition, stirred at 0° C. for 3hours, treated with saturated aqueous NH₄Cl solution (300 mL), andstirred for 5 minutes. The CH₂Cl₂ layer was isolated and the aqueouslayer was extracted with CH₂Cl₂ (2×150 mL). The combined CH₂Cl₂ layerswere dried (Na₂SO₄), filtered, and concentrated. The crude material waspurified by column chromatography (ethyl acetate/petroleum ether=1/200)to provide the title compound (6.8 g, 48.4 mmol, 71.3% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.19 (d, J=13.2 Hz, 1H), 6.83 (d, J=13.6 Hz, 1H),1.09 (s, 9H).

Intermediate 2 5-bromo-3-(bromomethyl)-2-methoxypyridine

To a solution of 5-bromo-2-methoxy-3-methylpyridine (Ark, 2.981 g, 14.75mmol) in CCl₄ (12 mL) was added N-bromosuccinimide (2.89 g, 16.23 mmol)and (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.036 g,0.221 mmol). The reaction mixture was stirred at 80° C. for 2 hours,cooled in an ice bath, and filtered through diatomaceous earth. Thesolution was concentrated in vacuo to afford the title compound (2.0538g, 50% yield). ¹H NMR (501 MHz, CDCl₃) δ ppm 8.17 (d, J=2.4 Hz, 1H),7.74 (d, J=2.4, 1H), 4.43 (s, 2H), 4.01 (s, 3H).

Intermediate 3 3-(bromomethyl)-2-methoxyquinoline Intermediate 3A(2-methoxyquinolin-3-yl)methanol

2-Methoxyquinoline-3-carbaldehyde (1.45 g, 7.75 mmol) was suspended inmethanol (20 mL) and the mixture was cooled to 0° C. Sodium borohydride(600 mg, 15.86 mmol) was added, causing bubbling. The reaction mixturewas stirred and gradually warmed to room temperature overnight (let icebath melt). The reaction mixture was concentrated, and the crudematerial was taken up in saturated aqueous bicarbonate solution (50 mL)and extracted with dichloromethane (2×50 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to afford thetitle compound (1.46 g, 7.72 mmol, 100% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.19 (q, J=1.2 Hz, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H),7.82-7.72 (m, 1H), 7.62 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.42 (ddd, J=8.1,6.9, 1.2 Hz, 1H), 5.44-5.30 (m, 1H), 4.66-4.54 (m, 2H), 4.01 (s, 3H); MS(ESI+) m/z 190 (M+H)⁺.

Intermediate 3B 3-(bromomethyl)-2-methoxyquinoline

Intermediate 3A (1.46 g, 7.72 mmol) and triphenylphosphine (4.00 g,15.25 mmol) were dissolved in dichloromethane (25 mL) and cooled in anice bath. N-bromosuccinimide (1.373 g, 7.72 mmol) was added graduallyusing a solid addition funnel, keeping the internal temperature below10° C. The ice bath was removed, and after stirring for 15 minutes thereaction was complete. The reaction was quenched by adding 10 mL ofwater, stirred for 5 minutes, and the layers were separated. The organiclayer was washed twice with water and filtered through a frittedcartridge layered with a pad of silica (1 cm), eluting with heptanes.The filtrates were reduced in volume to provide a solid which wasfiltered and washed with 3×30 mL of 50:50 methyl tert-butylether:heptanes. The material was dried in vacuo to provide a residue,and the residue was purified using a 40 g silica gel cartridge, elutingwith dichloromethane to provide the title compound (1.01 g, 4.01 mmol,51.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.35 (s, 1H), 7.86 (dd,J=8.1, 1.4 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.67 (ddd, J=8.3, 6.9, 1.5Hz, 1H), 7.44 (ddd, J=8.2, 6.8, 1.2 Hz, 1H), 4.74 (s, 2H), 4.05 (s, 3H);MS (ESI+) m/z 252 (M+H)⁺.

Intermediate 4 3-(bromomethyl)-5-cyclobutyl-2-methoxypyridineIntermediate 4A methyl 5-cyclobutyl-2-methoxynicotinate

Methyl 5-bromo-2-methoxynicotinate (CombiBlocks, 2.516 g, 10.23 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf), 0.383 g, 0.523 mmol) were suspended in tetrahydrofuran(100 mL), and the orange suspension was purged with N₂. A commercialsolution of cyclobutylzinc(II) bromide (Aldrich, 0.5 M tetrahydrofuran,24 mL, 12.00 mmol) was added dropwise, and the reaction mixture wasallowed to stir at room temperature for 16 hours. The reaction mixturewas quenched by the addition of 100 mL saturated aqueous ammoniumchloride, and the product was extracted into 300 mL of dichloromethane.The combined extracts were dried over sodium sulfate, filtered andconcentrated in vacuo. Silica gel chromatography, eluting with 5-100%ethyl acetate/heptanes, afforded the title compound (1.110 g, 49%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.16 (d, J=2.6 Hz, 1H), 8.05 (d,J=2.6 Hz, 1H), 4.04 (s, 3H), 3.93 (s, 3H), 3.53 (p, J=8.6 Hz, 1H),2.43-2.33 (m, 2H), 2.21-2.01 (m, 3H), 1.96-1.88 (m, 1H); MS (ESI+) m/z222 (M+H)⁺.

Intermediate 4B (5-cyclobutyl-2-methoxypyridin-3-yl)methanol

Intermediate 4A (1.110 g, 5.02 mmol) was dissolved in tetrahydrofuran(24 mL), and the solution was cooled in an ice bath. A solution oflithium aluminum hydride (2M in tetrahydrofuran, 2.51 mL, 5.02 mmol) wasadded dropwise over 3 minutes via syringe. The reaction mixture was thendiluted with 200 mL of methyl tert-butyl ether, quenched with 10 mL ofsaturated aqueous potassium sodium tartrate (Rochelle's salt), and themixture was stirred for another 30 minutes at room temperature beforeseparating the layers. The organic layer was dried over sodium sulfateand filtered, and the solvent was removed to provide the title compound,0.943 g (97% yield). The compound was dried azeotropically with tolueneand then used directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ ppm7.94 (d, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 4.67 (d, J=6.3 Hz, 2H),4.00 (d, J=0.8 Hz, 3H), 3.51 (p, J=8.5 Hz, 1H), 2.36 (dtd, J=10.3, 8.0,2.7 Hz, 2H), 2.29 (t, J=6.5 Hz, 1H), 2.22-2.00 (m, 3H), 1.97-1.84 (m,1H); MS (ESI+) m/z 194 (M+H)⁺.

Intermediate 4C 3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine

Intermediate 4B (0.943 g, 4.88 mmol) and triphenylphosphine (2.56 g,9.76 mmol) were dissolved in dichloromethane (24.4 mL) and cooled in anice bath. N-Bromosuccinimide (1.737 g, 9.76 mmol) was added graduallyusing a solid addition funnel, keeping the internal temperature below10° C. After completion of the addition, the ice bath was removed, andthe reaction was stirred at room temperature for 15 minutes. Water wasadded (10 mL), and the mixture was stirred for 5 minutes before thelayers were separated. The organic layer was washed twice with water andthen filtered through a fritted cartridge layered with a pad of silica(1 cm), eluting with heptanes. The filtrates were reduced in volume. Thesolid was collected by filtration and washed with 3×30 mL of 50:50methyl tert-butyl ether:heptanes. The filtrate was concentrated, and theresidue was purified by silica gel chromatography, eluting with 5-50%ethyl acetate/heptanes, to yield the title compound (1.07 g, 86% yield).¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (d, J=2.4 Hz, 1H), 7.52 (d, J=2.4 Hz,1H), 4.52 (s, 2H), 4.02 (s, 3H), 3.59-3.38 (m, 1H), 2.44-2.31 (m, 2H),2.21-2.00 (m, 3H), 1.95-1.85 (m, 1H); MS (ESI+) m/z 256 (M+H)⁺.

Intermediate 5 (S)-tetrahydro-2H-pyran-2-carboxylic acid Intermediate 5A(S)-4-benzyl-3-((S)-tetrahydro-2H-pyran-2-carbonyl)oxazolidin-2-oneIntermediate 5B(S)-4-benzyl-3-((R)-tetrahydro-2H-pyran-2-carbonyl)oxazolidin-2-one

Tetrahydro-2H-pyran-2-carboxylic acid (8.9 g, 68.4 mmol) was dissolvedin 15 mL of dichloromethane and oxalyl chloride (11.97 mL, 137 mmol) wasadded. Two drops of dimethylformamide were added to catalyze thereaction and it was stirred at room temperature for 1 hour beforeconcentrating in vacuo. The bath temperature was kept at 25° C. Thetetrahydro-2H-pyran-2-carbonyl chloride was azeotroped one time withtetrahydrofuran (30 mL), dissolved in 3 mL of tetrahydrofuran and usedimmediately in the coupling reaction.

(S)-4-Benzyloxazolidin-2-one (11.54 g, 65.1 mmol) was dissolved in 15 mLof tetrahydrofuran and n-butyllithium (25.9 mL, 65.1 mmol) was added,maintaining an internal temperature<−60° C. After the addition wascomplete, a solution of tetrahydro-2H-pyran-2-carbonyl chloride (10.16g, 68.4 mmol) in 3 mL of tetrahydrofuran was added dropwise, and slightexotherms were noted (<5° C.). TLC immediately after the addition wascomplete and showed complete conversion to the desired product. Thefirst eluting peak A was the desired (S) diastereomer using methyltert-butyl ether/heptanes. The crude 1:1 mix was loaded onto a 330 gsilica gel column, eluting with 0:100 to 50:50 methyl tert-butylether:heptanes over 30 minutes then isocratic 50:50 methyl tert-butylether:heptanes until the complete elution of the second diastereomer. Atotal of 8.9 g of the title compound was obtained. First eluting peak51A:(S)-4-benzyl-3-((S)-tetrahydro-2H-pyran-2-carbonyl)oxazolidin-2-one. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.42-7.17 (m, 5H), 5.05 (dd, J=10.5, 2.0 Hz,1H), 4.68 (ddt, J=10.1, 6.7, 3.4 Hz, 1H), 4.32-4.08 (m, 3H), 3.62 (td,J=11.5, 2.5 Hz, 1H), 3.38 (dd, J=13.4, 3.3 Hz, 1H), 2.79 (dd, J=13.4,9.7 Hz, 1H), 2.01-1.85 (m, 2H), 1.78-1.55 (m, 4H); MS (ESI+) m/z 290.0(M+H)⁺. Second-eluting peak 51B:(S)-4-benzyl-3-((R)-tetrahydro-2H-pyran-2-carbonyl)oxazolidin-2-one. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.43-7.17 (m, 5H), 4.96 (dd, J=10.5, 2.1 Hz,1H), 4.75 (ddt, J=9.2, 7.9, 3.3 Hz, 1H), 4.34-4.16 (m, 2H), 4.18-4.06(m, 1H), 3.58 (td, J=11.6, 2.6 Hz, 1H), 3.30-3.18 (m, 1H), 2.84 (dd,J=13.5, 9.2 Hz, 1H), 2.09-1.90 (m, 2H), 1.77-1.52 (m, 4H); MS (ESI+) m/z290.0 (M+H)⁺.

Intermediate 5C (S)-tetrahydro-2H-pyran-2-carboxylic acid

Lithium hydroxide hydrate (6.36 g, 152 mmol) was dissolved in 180 mL ofwater. A separate solution of(S)-4-benzyl-3-((S)-tetrahydro-2H-pyran-2-carbonyl)oxazolidin-2-one(27.4 g, 95 mmol) in 50 mL of tetrahydrofuran was prepared, and thesolution was cooled to 0° C. in an ice-water bath before adding hydrogenperoxide (30% aqueous) (36 mL, 352 mmol). Lithium hydroxide solution wasadded via syringe (over 30 minutes, maintaining an internal temperaturebelow 5° C.). The reaction was stirred at the same temperature for 90minutes, at which point it was complete. The reaction was quenched byaddition of aqueous sodium sulfite (48 g of Na₂SO₃ in 280 mL of water)slowly via addition funnel, maintaining an internal temperature below10° C. The tetrahydrofuran was removed in vacuo (water bath at 25° C.).The auxiliary was removed by extraction with dichloromethane (3×150 mL).To the aqueous layer was added 200 mL of dichloromethane and theresulting mixture was stirred in an ice-water bath while the aqueouslayer was acidified with 6M aqueous HCl via addition funnel. Theinternal temperature was maintained below 10° C. during the addition.The layers were separated, the aqueous layer was extracted withdichloromethane (9×150 mL), and the combined dichloromethane layers weredried over sodium sulfate, filtered, and concentrated to provide thedesired product. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.89 (s, 1H), 4.20-4.08(m, 1H), 4.04-3.85 (m, 1H), 3.54 (td, J=11.3, 2.7 Hz, 1H), 2.05 (dq,J=8.9, 3.6, 3.2 Hz, 1H), 1.92 (dqd, J=6.9, 5.3, 4.4, 1.7 Hz, 1H),1.69-1.45 (m, 4H). [α]23=−6.8° (c=1.0, methanol).

Intermediate 6 2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzeneIntermediate 6A (5-(tert-butyl)-2-methoxyphenyl)methanol

To a cooled (ice bath) solution of 5-tert-butyl-2-methoxybenzoic acid(0.828 g, 3.98 mmol) in tetrahydrofuran (19.88 mL) was added LAH(lithium aluminum hydride) (0.151 g, 3.98 mmol) in portions. The mixturewas allowed to warm to room temperature and was stirred for 1 hour.Additional lithium aluminum hydride was added (2 mL of a 2M solution intetrahydrofuran) and after 3 hours the reaction was quenched by slowaddition of sodium sulfate decahydrate. The mixture was diluted withether and was stirred at room temperature for 15 hours. The mixture wasfiltered and the solids were washed with ether (2×50 mL). The filtratewas concentrated to provide (5-(tert-butyl)-2-methoxyphenyl)methanol(0.770 g, 3.96 mmol, 100% yield), which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.35-7.27(m, 2H), 6.92-6.77 (m, 1H), 4.72 (d, J=6.2 Hz, 2H), 3.88 (s, 3H), 2.37(t, J=6.5 Hz, 1H), 1.34 (s, 9H); MS (ESI+) m/z 195 (M+H)⁺.

Intermediate 6B 2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene

Intermediate 6A (0.77 g, 3.96 mmol) was combined with triphenylphosphine(2.079 g, 7.93 mmol) and dissolved in dichloromethane (19.82 mL).N-Bromosuccinimide (1.411 g, 7.93 mmol) was added in several portionsand an exotherm/bubbling was noted (temperature did not exceed 23° C.).After stirring for 15 minutes, the reaction was quenched by adding 5 mLof water. The mixture was stirred for 5 minutes, the layers wereseparated, and the organic layer was washed twice with water andfiltered through a fritted cartridge layered with a pad of silica (2cm), eluting with heptanes. The filtrate was concentrated toapproximately 4 mL and was loaded directly onto a 40 g silica gel columnand eluted with 0-15% ethyl acetate/heptanes over 30 minutes to provide2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (0.250 g, 0.972 mmol,24.53% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.39 (d, J=2.5 Hz, 1H),7.17 (dd, J=8.5, 2.6 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.49 (s, 2H), 3.74(s, 3H), 1.26 (s, 9H).

Intermediate 7 3-(bromomethyl)-2-methoxyquinoline Intermediate 7A(2-methoxyquinolin-3-yl)methanol

2-Methoxyquinoline-3-carbaldehyde (1.45 g, 7.75 mmol) was suspended inmethanol (20 mL) and the mixture was cooled to 0° C. in an ice bath.Sodium borohydride (600 mg, 15.86 mmol) was added, causing bubbling. Thereaction mixture was stirred and was allowed to warm to room temperatureovernight (ice bath was allowed to melt). The reaction mixture wasconcentrated, and the crude material was taken up in saturated aqueousbicarbonate solution (50 mL) and was extracted with dichloromethane(2×50 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated to afford the product (1.46 g, 7.72 mmol, 100% yield).¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.19 (q, J=1.2 Hz, 1H), 7.90 (dd, J=8.0,1.5 Hz, 1H), 7.82-7.72 (m, 1H), 7.62 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.42(ddd, J=8.1, 6.9, 1.2 Hz, 1H), 5.44-5.30 (m, 1H), 4.66-4.54 (m, 2H),4.01 (s, 3H); MS (ESI+) m/z 190 (M+H)⁺.

Intermediate 7B 3-(bromomethyl)-2-methoxyquinoline

Intermediate 7A (1.46 g, 7.72 mmol) and triphenylphosphine (4.00 g,15.25 mmol) were dissolved in dichloromethane (25 mL) and cooled in anice bath. N-Bromosuccinimide (1.373 g, 7.72 mmol) was added graduallyusing a solid addition funnel, keeping the internal temperature below10° C. The ice bath was removed, and after stirring for 15 minutes thereaction was complete. The reaction was quenched by adding 10 mL ofwater. The mixture was stirred for 5 minutes. The layers were separatedand the organic layer was washed twice with water and filtered through afritted cartridge layered with a pad of silica (1 cm), eluting withheptanes. The filtrates were reduced in volume. The mixture was filteredand washed with 3×30 mL of 50:50 methyl tert-butyl ether:heptanes. Thesolvent was removed in vacuo, and the crude material was purified usinga 40 g silica gel cartridge eluting with dichloromethane to provide thetitle compound (1.01 g, 4.01 mmol, 51.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.35 (s, 1H), 7.86 (dd, J=8.1, 1.4 Hz, 1H), 7.77 (d,J=8.2 Hz, 1H), 7.67 (ddd, J=8.3, 6.9, 1.5 Hz, 1H), 7.44 (ddd, J=8.2,6.8, 1.2 Hz, 1H), 4.74 (s, 2H), 4.05 (s, 3H); MS (ESI+) m/z 252 (M+H)⁺.

Intermediate 8 3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridineIntermediate 8A methyl 2-methoxy-5-(trifluoromethyl)nicotinate

To 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (50 g, 195 mmol) andPd-dppf ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),Heraeus, 1.32 g, 1.804 mmol) in a 300 mL stainless steel reactor wasadded methanol (250 mL) and triethylamine (54.4 mL, 391 mmol). Thereactor was degassed with nitrogen several times and carbon monoxide andwas heated to 100±5° C. for 16.38 hours and at 60 psi.±4 psi for 2.7hours and 21±7 psi (˜14 hours). Additional Pd-dppf (Heraeus) (0.82 g,1.121 mmol) catalyst was added. The crude product was concentrated toremove methanol. Ethyl acetate (400 mL) was added, followed by additionof 150 mL of saturated aqueous NH₄Cl, and the organic layer wasisolated. The aqueous layer was extracted with ethyl acetate (200 mL).The organic layers were combined, washed with brine, dried over Na₂SO₄,filtered, and passed through a silica gel plug to remove dark Pt/C. Thefiltrate was concentrated to provide 40.62 g of the desired crudeproduct, which was used directly in the next step. ¹H NMR (400 MHz,DMSO-d₆) δ ppm=3.84 (s, 3H) 3.96 (s, 3H) 8.40 (br s, 1H) 8.81 (br s,1H); MS (ESI⁺) m/z 236.1 (M+H)⁺.

Intermediate 8B (2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol

Ethyl 2-methoxy-5-(trifluoromethyl)nicotinate (59.54 g, 253 mmol) wasdissolved in tetrahydrofuran (506 mL). After cooling to <5° C., asolution of lithium aluminum hydride (177 mL, 177 mmol) intetrahydrofuran was added over 40 minutes, maintaining an internaltemperature<10° C. After 1 hour, the reaction was quenched by theaddition of 50 mL of acetone, diluted with methyl tert-butyl ether (300mL) and stirred with 300 mL of saturated aqueous potassium sodiumtartrate (Rochelle's salt) until two clear layers were present. Thereaction mixture was extracted with ethyl acetate and the combinedextracts were washed with brine, dried over sodium sulfate, filtered,and concentrated to provide a residue, which was purified by flashchromatography (0 to 30% ethyl acetate in heptane) to provide(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol (40.28 g, 194 mmol,77% yield). ¹H NMR (400 MHz, 10740717-864-P1A, DMSO-d₆) δ ppm 3.96 (s,3H) 4.50 (d, J=5.73 Hz, 2H) 5.45 (t, J=5.73 Hz, 1H) 7.89-8.01 (m, 1H)8.47 (s, 1H); MS (ESI⁺) m/z 208.0 (M+H)⁺.

Intermediate 8C 3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine

Intermediate 8B (21.6 g, 104 mmol) and triphenylphosphine (54.7 g, 209mmol) were dissolved in dichloromethane (521 mL) and the reactionmixture was cooled to 0° C. N-Bromosuccinimide (37.1 g, 209 mmol) wasadded in several portions and an exotherm/bubbling was noted(temperature did not exceed 25° C.). After stirring for 5 minutes in theice bath, the reaction was warmed to room temperature for 30 minutes.The reaction mixture was cooled in the ice bath before addition of 300mL of water, stirred for 5 minutes, and the organic layer was separated.The organic layer was washed with water (2×30 mL) then concentrated toapproximately 50 mL and filtered through a fritted funnel layered with apad of silica (1.5 inch), eluting with heptanes. The filtrates wereconcentrated to provide a viscous mixture and were diluted with 50:50methyl tert-butyl ether:heptanes. The resulting solid was filtered. Thefiltrate was concentrated and was purified with a 330 g silica gelcartridge using a gradient of 5% ethyl acetate in heptane to providedesired product (22.12 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.04-4.10(m, 3H) 4.46-4.50 (m, 2H) 7.83 (d, J=2.43 Hz, 1H) 8.40 (d, J=1.10 Hz,1H).

Intermediate 9 5-bromo-3-(bromomethyl)-2-methoxypyridine

To a solution of 5-bromo-2-methoxy-3-methylpyridine (Ark, 2.981 g, 14.75mmol) in CCl₄ (12 mL) was added N-bromosuccinimide (2.89 g, 16.23 mmol)and (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.036 g,0.221 mmol). The reaction mixture was stirred at 80° C. for 2 hours, andcooled in an ice bath and filtered through diatomaceous earth. Thesolution was concentrated in vacuo to afford the title compound (2.0538g, 50% yield). ¹H NMR (501 MHz, CDCl₃) δ ppm 8.17 (d, J=2.4 Hz, 1H),7.74 (d, J=2.4, 1H), 4.43 (s, 2H), 4.01 (s, 3H).

Intermediate 10 3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridineIntermediate 10A (5-bromo-2-methoxypyridin-3-yl)methanol

5-Bromo-2-methoxynicotinaldehyde (2 g, 9.26 mmol) was suspended inmethanol (40 mL) and cooled to 0° C. Sodium borohydride (0.350 g, 9.26mmol) was added, causing bubbling. The reaction mixture was stirred at0° C. for 15 minutes, the flask was removed from the ice bath, and themixture was allowed to stir at room temperature for 2 hours. Thereaction mixture was concentrated, and the crude material was taken upin methyl tert-butyl ether and saturated aqueous sodium bicarbonate. Thephases were separated, and the organic layer was dried over Na₂SO₄,filtered and concentrated to afford the title compound (1.876 g, 8.60mmol, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.15 (d, J=2.5 Hz, 1H),7.75 (d, J=2.4 Hz, 1H), 4.66 (d, J=6.2 Hz, 2H), 3.99 (s, 3H), 2.15 (t,J=6.3 Hz, 1H); MS (DCI+) m/z 217.8 (M+H)⁺.

Intermediate 10B5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine

(5-Bromo-2-methoxypyridin-3-yl)methanol (1.876 g, 8.60 mmol),tert-butyldimethylsilyl chloride (1.556 g, 10.32 mmol), and imidazole(0.879 g, 12.91 mmol) were stirred in dichloromethane (35 mL) overnightat room temperature. Methanol (3 mL) was added to quench thetert-butyldimethylsilyl chloride, and the reaction mixture was stirredat room temperature for 10 minutes. The mixture was diluted withdichloromethane and washed twice with saturated aqueous sodiumbicarbonate and once with brine. The organic layer was dried over sodiumsulfate, filtered and concentrated to afford5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine (2.71g, 8.16 mmol, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (dt, J=2.5,0.9 Hz, 1H), 7.81 (dt, J=2.5, 1.2 Hz, 1H), 4.65 (m, 2H), 3.93 (s, 3H),0.93 (s, 9H), 0.14 (s, 6H); MS (ESI+) m/z 332 (M+H)⁺.

Intermediate 10C5-(tert-butyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine

A 50 mL round bottom flask containing a solution of5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine(1.624 g, 4.89 mmol) in tetrahydrofuran (12.22 mL) was degassed bybubbling nitrogen through the mixture for 20 minutes. To this solutionwas added nickel chloride dimethoxyethane adduct (0.107 g, 0.489 mmol)and 1,3-dicyclohexyl-1H-imidazol-3-ium tetrafluoroborate (0.156 g, 0.489mmol) and degassing continued for another 15 minutes. The reaction wascooled to −10° C. tert-Butylmagnesium chloride (1M in tetrahydrofuran)(9.77 mL, 9.77 mmol) was added dropwise. The reaction was stirred at−10° C. for 100 minutes. The reaction was quenched with chips of ice andwas allowed to warm to room temperature. The mixture was poured intosaturated aqueous NH₄Cl solution and was extracted three times withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. The crude materialwas purified using an 80 g silica gel cartridge, eluting with 0 to 50%methyl tert-butyl ether-heptanes over 40 minutes to provide5-(tert-butyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine(1.12 g, 3.62 mmol). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.06 (dt, J=2.7, 0.8Hz, 1H), 7.82 (dt, J=2.4, 1.2 Hz, 1H), 4.71 (t, J=1.0 Hz, 2H), 3.95 (s,3H), 1.34 (s, 9H), 1.02-0.95 (m, 15H).

Intermediate 10D (5-(tert-butyl)-2-methoxypyridin-3-yl)methanol

5-(tert-Butyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine(1.124 g, 3.63 mmol) was dissolved in tetrahydrofuran (22 mL) andtreated with tetrabutylammonium fluoride trihydrate (2.19 g, 6.94 mmol),and the reaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was poured into saturated aqueous NH₄Cl, and themixture was extracted three times with ethyl acetate. The combinedextracts were dried over Na₂SO₄, filtered, and concentrated. The crudematerial was purified using a 40 g silica gel cartridge with a gradientof 5-100% ethyl acetate/heptanes over 40 minutes to provide(5-(tert-butyl)-2-methoxypyridin-3-yl)methanol (0.6128 g, 3.14 mmol, 86%yield). H NMR (400 MHz, CDCl₃) δ ppm 8.10 (d, J=2.5 Hz, 1H), 7.70-7.53(m, 1H), 4.65 (d, J=5.3 Hz, 2H), 3.98 (s, 3H), 2.52-2.37 (m, 1H), 1.32(s, 9H).

Intermediate 10E 3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine

(5-(tert-Butyl)-2-methoxypyridin-3-yl)methanol (0.502 g, 2.57 mmol) andtriphenylphosphine (1.349 g, 5.14 mmol) were dissolved indichloromethane (12.85 mL). N-Bromosuccinimide (0.915 g, 5.14 mmol) wasadded in several portions and an exotherm/bubbling were noted (temp didnot exceed 23° C.). After stirring for 15 minutes, the reaction wasquenched by adding 5 mL of water. The mixture was stirred for 5 minutesand the layers were separated. The organic layer was washed twice withwater, and filtered through a fritted cartridge layered with a pad ofsilica (2 cm), eluting with heptanes. The filtrates were concentrated,triturated with 50:50 methyl tert-butyl ether:heptanes, and filtered.The solid was washed with 50:50 methyl tert-butyl ether/heptanes (2×10mL) and the solvent was removed in vacuo to provide3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine (0.582 g, 2.254 mmol,88% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.14 (d, J=2.6 Hz, 1H), 7.63(d, J=2.6 Hz, 1H), 4.50 (s, 2H), 4.01 (s, 3H), 1.33 (s, 9H).

Core Synthesis Core 1 rac-(2R,3R,4R,5R)-ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate Core 1A(E)-ethyl 2-(benzylideneamino)acetate

To a mixture of glycine ethyl ester hydrochloride (7.23 g, 51.8 mmol)and magnesium sulfate (7.09 g, 58.9 mmol) in dichloromethane (80 mL) wasadded triethylamine (7.22 mL, 51.8 mmol). The mixture was stirred atambient temperature for 20 minutes, and benzaldehyde (4.79 mL, 47.1mmol) was added dropwise. The mixture was stirred overnight. Thereaction mixture was filtered and the solid was washed withdichloromethane (20 mL×2). The combined organic layers were washed withbrine, dried over MgSO₄, filtered and concentrated to yield (E)-ethyl2-(benzylideneamino)acetate 8.2 g, (91% yield). ¹H NMR (400 MHz, CDCl₃)δ ppm 8.30 (s, 1H), 7.83-7.71 (m, 2H), 7.48-7.37 (m, 2H), 4.40 (d, J=1.4Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H); MS (ESI+) m/z292.1 (M+H)⁺.

Core 1B rac-(2R,3R,4R,5R)-ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

To a solution of Core 1A (1.0 g, 5.23 mmol) and(E)-3,3-dimethyl-1-nitrobut-1-ene (0.810 g, 6.28 mmol) in toluene (30mL) cooled in an ice-bath was added acetyl(oxo)silver (1.309 g, 7.84mmol) and 3 Å molecular sieves. Triethylamine (1.458 mL, 10.46 mmol) wasadded slowly to the well stirred reaction mixture. After stirring at 0°C. for 10 minutes, the reaction mixture was allowed to warm to ambienttemperature and was stirred for another 4 hours. Saturated aqueousammonium chloride was added, the precipitate was filtered off and theresidue was extracted with ether. The combined organic fractions weredried over MgSO₄, filtered, concentrated, and purified by chromatographyon 40 g silica gel cartridge, eluting with ethyl acetate in heptane,0-40% gradient to provide the title compound (1.6 g, 95% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.39-7.26 (m, 5H), 5.12 (dd, J=6.0, 2.5 Hz, 1H),4.44 (d, J=5.7 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.81 (d, J=7.1 Hz, 1H),3.30 (s, 1H), 2.95 (dd, J=7.1, 2.5 Hz, 1H), 1.34 (t, J=7.2 Hz, 3H), 1.06(s, 9H); MS(ESI+) m/z 321 (M+H)⁺.

Core 2 rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-nitropyrrolidine-2-carboxylate Core2A (E)-ethyl 2-((2-methoxybenzylidene)amino)acetate

To a mixture of ethyl 2-aminoacetate hydrochloride (10.76 g, 77.12 mmol)and magnesium sulfate (10.61 g, 88.2 mmol) in dichloromethane (100 mL)was added triethylamine (11.2 mL, 80.8 mmol). The mixture was stirred atroom temperature for 20 minutes and then 2-methoxybenzaldehyde (10.0 g,73.45 mmol) was added dropwise. The resulting mixture was stirred atroom temperature overnight. The solid was filtered off and washed withdichloromethane (300 mL). The combined filtrate was washed with water(150 mL) and brine (150 mL), dried over magnesium sulfate, filtered andconcentrated to provide the title compound (E)-ethyl2-((2-methoxybenzylidene)amino)acetate (16 g, 50.60 mmol, 68.9% yield).¹H NMR (400 MHz, CDCl₃) δ ppm 8.73 (s, 1H), 8.01 (d, J=8.0 Hz, 1H),7.37-7.44 (m, 1H), 6.89-7.00 (m, 2H), 4.40 (s, 2H), 4.20-4.26 (m, 2H),3.85 (s, 3H), 1.28-1.31 (m, 3H).

Core 2B rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-nitropyrrolidine-2-carboxylate

To a solution of (E)-ethyl 2-((2-methoxybenzylidene)amino)acetate (26.72g, 120.94 mmol) and lithium bromide (13.90 g, 131.02 mmol) intetrahydrofuran (220 mL) at −78° C. was added(E)-3,3-dimethyl-1-nitrobut-1-ene (13.0 g, 110.78 mmol) intetrahydrofuran (20 mL) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene,22.6 mL, 151.18 mmol) dropwise. The mixture was stirred at −78° C. for2.5 hours and quenched with saturated aqueous ammonium chloride (100mL), extracted with ethyl acetate (2×150 mL), washed with brine (2×150mL), dried over sodium sulfate, filtered and concentrated. The residuewas triturated with petroleum ether (100 mL). The solid was collected byfiltration and dried in vacuo to provide the title compoundrac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-nitropyrrolidine-2-carboxylate(10.3 g, 29.43 mmol, 28.3% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm7.22-7.28 (m, 2H), 6.86-6.95 (m, 2H), 5.33-5.35 (m, 1H), 4.56 (s, 1H),4.30-4.32 (m, 2H), 3.89 (s, 3H), 3.77 (d, J=8.0 Hz, 1H), 3.36 (d, J=7.2Hz, 1H), 2.88-2.90 (m, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.05 (s, 9H); LC-MS(ESI+) m/z 351 (M+H)⁺.

Core 3 (2R,3S,4R,5R)-benzyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate Core 3A(E)-benzyl 2-(benzylideneamino)acetate

To the mixture of benzyl 2-aminoacetate hydrochloride (CAS#2462-31-9) (5g, 21.00 mmol) and magnesium sulfate (3.16 g, 26.2 mmol) indichloromethane (80 mL) was added triethylamine (3.22 mL, 23.10 mmol).The mixture was stirred for 20 minutes, benzaldehyde (2.348 mL, 23.10mmol) was added dropwise, and the mixture was stirred at ambienttemperature overnight. The mixture was filtered and the solid was washedwith dichloromethane. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated to yield (E)-benzyl2-(benzylideneamino)acetate (5.3 g, 100% yield). ¹H NMR (400 MHz, CDCl₃)δ ppm 8.28 (s, 1H), 7.84-7.70 (m, 2H), 7.48-7.26 (m, 8H), 5.21 (s, 2H),4.44 (d, J=1.3 Hz, 2H); MS (ESI+) m/z 254 (M+H)⁺.

Core 3B rac-(2R,3S,4R,5R)-benzyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

The title compound was synthesized with the same procedure as Core 1Busing Core 3A as starting material. LC/MS (ESI+) m/z 378.37 (M+H)⁺.

Core 4 rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-5-(2-(dimethylamino)pyridin-3-yl)-4-nitropyrrolidine-2-carboxylateCore 4A 2-(dimethylamino)nicotinaldehyde

Dimethylamine (aqueous solution, 10 mL, 79 mmol) was diluted with 10 mLof methanol and 2-chloronicotinaldehyde (5.0 g, 35.3 mmol) was added allat once. The reaction mixture was heated to 55° C. for 24 hours andanother 10 mL of dimethylamine solution was added. After an additional24 hours, the starting material had been consumed. The reaction mixturewas cooled to room temperature, diluted with saturated aqueous ammoniumchloride and extracted with dichloromethane. The combined extracts wereconcentrated and purified via flash chromatography, eluting with 0-20%ethyl acetate/heptanes over 20 minutes on an 80 g silica gel column toprovide the title compound (3.9988 g, 75%). ¹H NMR (501 MHz, CDCl₃) δppm 9.96 (s, 1H), 8.31 (dd, J=4.6, 2.0 Hz, 1H), 7.94 (dd, J=7.6, 2.0 Hz,1H), 6.77 (dd, J=7.6, 4.6 Hz, 1H), 3.13 (s, 6H); LC-MS (ESI+) m/z 151.1(M+H)⁺.

Core 4B (E)-ethyl2-(((2-(dimethylamino)pyridin-3-yl)methylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (3.72 g, 26.6 mmol) and magnesiumsulfate (6.41 g, 53.3 mmol) were suspended in dichloromethane (44.4 mL).The suspension was treated with 2-(dimethylamino)nicotinaldehyde (4 g,26.6 mmol) and triethylamine (3.71 mL, 26.6 mmol) and the mixture wasstirred at room temperature for 16 hours. The solid material was removedvia filtration and the filtrate was washed with water, dried over sodiumsulfate, filtered and concentrated to provide the crude imine (5.76 g,92%), which was used in the next step without additional purification.¹H NMR (400 MHz, CDCl₃) δ ppm 8.42-8.37 (m, 1H), 8.26 (dd, J=4.8, 2.0Hz, 1H), 8.06 (dd, J=7.6, 1.9 Hz, 1H), 6.84 (ddd, J=7.6, 4.8, 0.6 Hz,1H), 4.40 (d, J=1.3 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 2.97 (s, 6H), 1.29(t, J=7.1 Hz, 3H).

Core 4C rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-5-(2-(dimethylamino)pyridin-3-yl)-4-nitropyrrolidine-2-carboxylate

(E)-Ethyl 2-(((2-(dimethylamino)pyridin-3-yl)methylene)amino)acetate(3.31 g, 14.07 mmol) was dissolved in 60 mL of tetrahydrofuran. Theresulting solution was cooled in an acetone-dry ice bath to −78° C.before adding (E)-3,3-dimethyl-1-nitrobut-1-ene (1.58 g, 12.23 mmol),and lithium bromide (10.60 mL, 15.90 mmol).2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine (2.104 mL, 14.07 mmol)was added dropwise via syringe, and the resulting mixture was stirred at−78° C. for 2 hours then warmed to ambient temperature before quenchingwith saturated aqueous ammonium chloride (30 mL). The mixture wasextracted with 3×15 mL of methyl tert-butyl ether and was concentratedin vacuo to provide crude material, which was purified via flashchromatography, eluting with 0:100 to 30:70 ethyl acetate:heptanes over20 minutes on an 80 g silica gel column to provide 2.20 g of the titlecompound. ¹H NMR (501 MHz, CDCl₃) δ ppm 8.30 (dd, J=4.8, 1.8 Hz, 1H),7.62 (ddd, J=7.6, 1.8, 0.8 Hz, 1H), 6.99 (dd, J=7.7, 4.8 Hz, 1H), 5.48(dd, J=5.7, 2.4 Hz, 1H), 4.62 (dd, J=12.3, 5.7 Hz, 1H), 4.31 (qd, J=7.2,1.6 Hz, 2H), 3.80 (dd, J=9.7, 7.1 Hz, 1H), 3.18 (t, J=11.2 Hz, 1H),2.94-2.90 (m, 1H), 2.79 (s, 6H), 1.34 (t, J=7.1 Hz, 3H), 1.07 (s, 10H);MS (ESI+) m/z 365.2 (M+H)⁺.

Core 5 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate Core 5A(E)-ethyl 2-(benzylideneamino)acetate

Ethyl 2-aminoacetate hydrochloride (30 g, 215 mmol) and magnesiumsulfate (51.7 g, 430 mmol) were stirred in dichloromethane (358 mL) atambient temperature, and triethylamine (30.0 mL, 215 mmol) was added.The resulting suspension was stirred for 5 minutes and benzaldehyde(21.78 mL, 215 mmol) was added dropwise via syringe. The mixture wasthen stirred at ambient temperature for 16 hours. The solid material wasremoved via filtration through a fritted funnel, and the filter cake waswashed with 20 mL of dichloromethane. The filtrate was washed with 2×20mL of water, dried over sodium sulfate, filtered, and concentrated toprovide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 8.30 (d, J=1.4Hz, 1H), 7.82-7.74 (m, 2H), 7.50-7.36 (m, 3H), 4.40 (d, J=1.3 Hz, 2H),4.24 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

Core 5B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(2.98 g, 3.96 mmol) and copper (I) triflate dimer, benzene complex(0.859 g, 1.707 mmol; 90% technical grade, Aldrich) were dissolved intetrahydrofuran (697 mL) that had been sparged with a nitrogen streamfor 2 hours. The resulting mixture was stirred for 90 minutes at ambienttemperature, at which point the flask was cooled to an internaltemperature below 5° C. (E)-Ethyl 2-(benzylideneamino)acetate (73.3 g,383 mmol) was added in one portion via syringe. Potassium2-methylpropan-2-olate (2.73 mL, 2.73 mmol, 1M solution intetrahydrofuran) was added dropwise, followed by addition of(E)-3,3-dimethyl-1-nitrobut-1-ene (45 g, 348 mmol) neat over 25 minutesvia syringe, maintaining an internal temperature<10° C. After theaddition was complete, the reaction was stirred for an additional 5minutes at the same temperature, at which point LC-MS showed completeconversion of the starting nitroalkene. The reaction mixture was dilutedwith 300 mL of methyl tert-butyl ether and stirred with 300 mL ofsaturated aqueous ammonium chloride at ambient temperature for 15minutes. The layers were separated, and the organic layer was washedwith saturated aqueous ammonium chloride and brine and dried over sodiumsulfate. After filtration, the organic extracts were concentrated invacuo to provide a crude residue (140 g), which was precipitated from800 mL of heptanes. The resulting material was removed via filtrationusing a fritted funnel, washed with 200 mL of cold heptanes, and driedto constant weight in a vacuum oven to provide 72.5 g of the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.37-7.18 (m, 5H), 5.13 (dd,J=6.0, 2.5 Hz, 1H), 4.45 (dd, J=12.4, 6.0 Hz, 1H), 4.32 (qd, J=7.2, 1.2Hz, 2H), 3.82 (dd, J=9.7, 7.1 Hz, 1H), 3.30 (dd, J=12.3, 9.8 Hz, 1H),2.96 (dd, J=7.2, 2.5 Hz, 1H), 1.35 (t, J=7.1 Hz, 3H), 1.06 (s, 9H); MS(ESI+) m/z 321.1 (M+H)⁺; [α]^(24.8)=+16.1° (c=1, methanol).

Core 6 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-fluorophenyl)-4-nitropyrrolidine-2-carboxylate Core6A (E)-ethyl 2-((2-fluorobenzylidene)amino)acetate

To a mixture of ethyl 2-aminoacetate hydrochloride (11.8 g, 84.7 mmol)and magnesium sulfate (11.7 g, 96.7 mmol) in dichloromethane (100 mL)was added triethylamine (12.5 mL, 88.7 mmol). The mixture was stirredfor 20 minutes and 2-fluorobenzaldehyde (10.0 g, 80.6 mmol) was addeddropwise. The resulting mixture was stirred at room temperatureovernight. The solid was filtered off and washed with dichloromethane(200 mL). The filtrate was washed with water (100 mL) and brine (100mL), dried over MgSO₄, filtered and concentrated to give the titlecompound (E)-ethyl 2-((2-fluorobenzylidene)amino)acetate (16.0 g, 76.6mmol, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.60 (s, 1H), 8.03-8.07(m, 1H), 7.39-7.45 (m, 1H), 7.11-7.20 (m, 1H), 7.06-7.08 (m, 1H), 4.43(s, 2H), 4.27, 4.24 (dd, J=7.2 Hz, 14.4 Hz, 2H), 1.32-1.36 (m, 3H),1.26-1.33 (m, 3H); LC-MS (ESI+) m/z 210 (M+H)⁺.

Core 6B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-fluorophenyl)-4-nitropyrrolidine-2-carboxylate

To a flame-dried Schlenk tube charged with activated 4 Å molecularsieves and a stirring bar was added [Cu(OTf)]₂.benzene (copper(II)trifluoromethanesulfonate, 417.8 mg, 0.83 mmol) and(2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(1.45 g, 1.93 mmol) in freshly distilled anhydrous tetrahydrofuran (160mL) under an inert atmosphere. The mixture was stirred for 15 minutesand cooled to 0° C. (E)-Ethyl 2-((2-fluorobenzylidene) amino) acetate(16.0 g, 76.6 mmol) was added, followed by addition of potassiumtert-butoxide (1.33 mL, 1.33 mmol) and (E)-3,3-dimethyl-1-nitrobut-1-ene(8.56 g, 66.36 mmol). The reaction mixture was stirred at 0° C. for 2hours, and then filtered through a short plug of silica gel. Thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (eluted with 10% petroleum ether/ethyl acetate) toprovide the title compound (13.55 g, 40.09 mmol, 58.6% yield, ee=95.3%).¹H NMR (400 MHz, CDCl₃) δ ppm 7.30-7.33 (m, 2H), 7.15-7.17 (m, 1H), 7.07(t, J=8.4 Hz, 1H), 5.22-5.24 (m, 1H), 4.60 (t, J=6.0 Hz, 1H), 4.29-4.35(m, 2H), 3.80 (t, J=3.6 Hz, 1H), 3.33 (t, J=11.2 Hz, 1H), 2.93-2.96 (m,1H), 1.35 (t, J=7.2 Hz, 3H), 1.06 (s, 9H); LC-MS(ESI+) m/z 339 (M+H)⁺.

Core 7 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-nitropyrrolidine-2-carboxylateCore 7A (E)-ethyl 2-(((2-isopropoxypyridin-3-yl)methylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (4.97 g, 35.6 mmol) and magnesiumsulfate (6.86 g, 57.0 mmol) were suspended in dichloromethane (47.5 mL)and the suspension was treated with 2-isopropoxynicotinaldehyde (4.8 g,28.5 mmol) and triethylamine (4.96 mL, 35.6 mmol). The mixture wasstirred for 16 hours at room temperature. The solid material was removedvia filtration and the filtrate was washed with water (twice) and brine,dried over sodium sulfate, filtered and concentrated to provide thecrude (E)-ethyl 2-(((2-isopropoxypyridin-3-yl)methylene)amino)acetate(7.14 g, 28.5 mmol, 100% yield), which was used without additionalpurification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.51 (s, 1H), 8.25 (dd,J=4.9, 2.0 Hz, 1H), 8.13 (dd, J=7.5, 2.1 Hz, 1H), 7.00 (ddd, J=7.5, 4.9,0.7 Hz, 1H), 5.34 (hept, J=6.2 Hz, 1H), 4.41 (d, J=1.3 Hz, 2H),4.15-3.99 (m, 2H), 1.30 (d, J=6.2 Hz, 6H), 1.18 (t, J=7.1 Hz, 3H). MS(DCI+) m/z 251.0 (M+H)⁺.

Core 7B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.141 g, 0.187 mmol) and copper (I) triflate dimer, benzene complex(0.036 g, 0.072 mmol) were dissolved in tetrahydrofuran (22.13 mL) thathad been sparged with a nitrogen stream for 2 hours. The resultingmixture was stirred for 1.5 hours at room temperature, and neat(E)-ethyl 2-(((2-isopropoxypyridin-3-yl)methylene)amino)acetate (3.6 g,14.38 mmol) was added after cooling to <5° C. in an ice-water bath.Potassium 2-methylpropan-2-olate (0.144 mL, 0.144 mmol) was added dropwise, followed by addition of neat (E)-3,3-dimethyl-1-nitrobut-1-ene(1.858 g, 14.38 mmol) over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete, the reaction mixturewas stirred for 15 minutes at the same temperature. The reaction mixturewas diluted with methyl tert-butyl ether (100 mL) and stirred with 75 mLof saturated aqueous ammonium chloride at room temperature for 15minutes. The organic layer was separated and washed with saturatedsodium bicarbonate solution and brine, dried over sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (0 to 20% ethyl acetate in heptane) to provide titlecompound (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-nitropyrrolidine-2-carboxylatecarboxylate (4.51 g, 11.89 mmol, 83% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 8.04 (dd, J=5.0, 1.8 Hz, 1H), 7.64 (dt, J=7.4, 1.4 Hz, 1H), 6.90(dd, J=7.3, 5.0 Hz, 1H), 5.33-5.19 (m, 2H), 4.41 (dd, J=9.5, 6.1 Hz,1H), 4.19 (qd, J=7.1, 5.3 Hz, 2H), 3.77 (dd, J=8.4, 7.3 Hz, 1H), 3.55(t, J=8.9 Hz, 1H), 2.92 (dd, J=7.3, 2.6 Hz, 1H), 1.32 (dd, J=13.6, 6.1Hz, 6H), 1.23 (t, J=7.1 Hz, 3H), 0.95 (s, 9H). MS (ESI⁺) m/z 380.0(M+H)⁺.

Core 8 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chlorophenyl)-4-nitropyrrolidine-2-carboxylate Core8A (E)-ethyl 2-((3-chlorobenzylidene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (5.96 g, 42.7 mmol) and magnesiumsulfate (5.14 g, 42.7 mmol) were suspended in dichloromethane (50.8 mL).Triethylamine (5.95 mL, 42.7 mmol) was added, and the reaction mixturewas stirred for 1 hour at ambient temperature before addition of3-chlorobenzaldehyde (4.03 mL, 35.6 mmol) via syringe. The reactionmixture was stirred overnight at ambient temperature. Solids wereremoved via filtration using a fritted funnel and the filter cake waswashed with dichloromethane (10 mL). The filtrate was quickly washedtwice with 10 mL of water and 10 mL of brine and dried over sodiumsulfate, filtered and concentrated in vacuo to provide a residue, whichwas used without additional purification. ¹H NMR (400 MHz, CDCl₃) δ ppm8.24 (d, J=1.3 Hz, 1H), 7.81 (t, J=1.8 Hz, 1H), 7.62 (dt, J=7.6, 1.4 Hz,1H), 7.48-7.29 (m, 2H), 4.40 (d, J=1.3 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H),1.31 (t, J=7.1 Hz, 3H).

Core 8B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chlorophenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.192 g, 0.255 mmol) and copper (I) triflate dimer, benzene complex(0.056 g, 0.111 mmol) were dissolved in tetrahydrofuran (50 mL) that hadbeen sparged with an N₂ stream for 1 hour. The resulting mixture wasstirred for 1 hour at ambient temperature, and 4 Å molecular sieves (6g, 22.16 mmol) were added, followed by addition of the (E)-ethyl2-((3-chlorobenzylidene)amino)acetate (6.0 g, 26.6 mmol) as a solutionin 3 mL of tetrahydrofuran. The resulting suspension was cooled to <5°C. in an ice-water bath. Potassium 2-methylpropan-2-olate (0.177 mL,0.177 mmol) was added dropwise, followed by addition of(E)-3,3-dimethyl-1-nitrobut-1-ene (2.86 g, 22.16 mmol) as a solution in2 mL of tetrahydrofuran over 10 minutes, maintaining a temperature lessthan 10° C. The reaction was complete after 10 minutes at the sametemperature as determined by LC-MS. The reaction was quenched with 5 mLof saturated aqueous ammonium chloride and filtered through diatomaceousearth after diluting with methyl tert-butyl ether (50 mL). The filtratewas stirred at ambient temperature with saturated aqueous ammoniumchloride (20 mL) for 15 minutes and the layers were separated. Theorganic layer was washed with saturated ammonium chloride and brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude material was loaded onto a 120 g silica gel column and was elutedwith 0:100 to 30:70 methyl tert-butyl ether:heptanes over 20 minutes toprovide 5.83 g of the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.33(dq, J=1.7, 1.0 Hz, 1H), 7.30-7.24 (m, 2H), 7.22-7.16 (m, 1H), 5.11 (dd,J=6.0, 2.5 Hz, 1H), 4.40 (dd, J=12.0, 6.0 Hz, 1H), 4.31 (qd, J=7.1, 1.1Hz, 2H), 3.79 (dd, J=9.6, 7.1 Hz, 1H), 3.21 (dd, J=11.9, 9.7 Hz, 1H),2.96 (dd, J=7.2, 2.6 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H), 1.05 (s, 9H). MS(ESI+) m/z 355.1 (M+H)⁺.

Core 9 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(o-tolyl)pyrrolidine-2-carboxylate Core 9A(E)-ethyl 2-((2-methylbenzylidene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (3.97 g, 28.5 mmol) and magnesiumsulfate (3.43 g, 28.5 mmol) were stirred in dichloromethane (43.1 mL) atambient temperature, and triethylamine (3.97 mL, 28.5 mmol) was added.The mixture was stirred for 5 minutes and 2-methylbenzaldehyde (2.97 mL,25.9 mmol) was added dropwise. The mixture was stirred at ambienttemperature for 16 hours. The solid material was filtered through adisposable plastic frit and washed with dichloromethane. The organiclayer was washed with 30 mL of water, dried over sodium sulfate,filtered, and concentrated. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.63 (d, J=1.4Hz, 1H), 7.96 (dd, J=7.7, 1.4 Hz, 1H), 7.35 (td, J=7.5, 1.5 Hz, 1H),7.32-7.25 (m, 1H), 7.25-7.18 (m, 1H), 4.45 (d, J=1.4 Hz, 2H), 4.28 (q,J=7.2 Hz, 2H), 2.55 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 206(M+H)⁺.

Core 9B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(o-tolyl)pyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.222 g, 0.294 mmol) and copper (I) triflate dimer, benzene complex(0.064 g, 0.127 mmol) were dissolved in tetrahydrofuran (51.7 mL) thathad been sparged with a stream of nitrogen for 4 hours. The resultingmixture was stirred for 1.5 hours at ambient temperature, and (E)-ethyl2-((2-methylbenzylidene)amino)acetate (5.31 g, 25.9 mmol) was addedafter cooling to <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate (0.203 mL, 0.203 mmol) was added dropwise,followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene (3.51 g, 27.2mmol) neat over 25 minutes, maintaining an internal temperature<10° C.After the addition was complete, the reaction was stirred for 90 minutesat the same temperature. The reaction mixture was diluted with methyltert-butyl ether (100 mL) and stirred with 50 mL of saturated aqueousammonium chloride at ambient temperature for 15 minutes. The organiclayer was washed with saturated sodium bicarbonate and brine, dried oversodium sulfate, and filtered. The filtrate was concentrated and wasdiluted with 80 mL of heptanes and the solvent was reduced in volumeuntil a solid precipitated out. The mixture was cooled in an ice bath to<5° C. for 15 minutes, and the resulting material was filtered, washedwith 20 mL of heptanes, and dried to constant weight in a vacuum oven toprovide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(o-tolyl)pyrrolidine-2-carboxylate (4.85 g,14.50 mmol, 56% yield). ¹H NMR (501 MHz, CDCl₃) δ ppm 7.34-7.27 (m, 1H),7.27-7.16 (m, 3H), 5.18 (dd, J=6.1, 2.6 Hz, 1H), 4.55 (dd, J=10.1, 5.9Hz, 1H), 4.35 (qd, J=7.2, 1.2 Hz, 2H), 3.81 (t, J=7.1 Hz, 1H), 3.31 (s,1H), 3.07 (dd, J=7.3, 2.6 Hz, 1H), 2.41 (s, 3H), 1.38 (t, J=7.1 Hz, 3H),1.08 (s, 9H). MS (APCI+) m/z 335 (M+H)⁺.

Core 10 (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-2-carboxylate Core10A (E)-ethyl 2-((2-bromobenzylidene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (2.63 g, 18.85 mmol) and magnesiumsulfate (2.269 g, 18.85 mmol) were stirred in dichloromethane (28.6 mL)at ambient temperature, and triethylamine (2.63 mL, 18.85 mmol) wasadded. The mixture was stirred for 5 minutes, 2-bromobenzaldehyde (2.0mL, 17.13 mmol) was added dropwise, and the mixture was stirred atambient temperature for 16 hours. The solid material was filteredthrough a disposable plastic frit and washed with dichloromethane. Theorganic layer was washed with 30 mL of water then dried over sodiumsulfate, filtered, and concentrated to provide (E)-ethyl2-((2-bromobenzylidene)amino)acetate (4.6 g, 17.03 mmol, 99% yield). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.70 (d, J=1.6 Hz, 1H), 8.12 (dd, J=7.7, 1.9Hz, 1H), 7.60 (dd, J=7.8, 1.3 Hz, 1H), 7.38 (tt, J=7.6, 1.1 Hz, 1H),7.35-7.27 (m, 1H), 4.48 (d, J=1.4 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.34(t, J=7.1 Hz, 3H); MS (ESI+) m/z 270 (M+H)⁺.

Core 10B (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.147 g, 0.195 mmol) and copper (I) triflate dimer, benzene complex(0.042 g, 0.084 mmol) were dissolved in tetrahydrofuran (34.3 mL) thathad been sparged with stream of nitrogen for 1 hour. The resultingmixture was stirred for 1.5 hours at ambient temperature, and (E)-ethyl2-((2-bromobenzylidene)amino)acetate (4.63 g, 17.14 mmol) was addedafter cooling to <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate (0.134 mL, 0.134 mmol) was added dropwise,followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene (2.324 g,18.00 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete and stirred for 90minutes, LC-MS showed complete conversion. The mixture was diluted withmethyl tert-butyl ether (150 mL) and stirred with 50 mL of saturatedaqueous ammonium chloride at ambient temperature for 15 minutes. Thelayers were separated and the organic layer was washed with saturatedaqueous sodium bicarbonate and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated, and precipitated from 50 mLof heptane. The mixture was cooled in an ice bath to <5° C. for 15minutes, and the resulting material was filtered and washed with 20 mLof heptanes to provide (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-2-carboxylate (4.303g, 10.78 mmol, 62.9% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.58 (dd,J=8.0, 1.2 Hz, 1H), 7.41-7.29 (m, 2H), 7.24-7.14 (m, 1H), 5.43 (dd,J=5.9, 2.3 Hz, 1H), 4.70 (dd, J=10.7, 5.9 Hz, 1H), 4.33 (qd, J=7.1, 1.2Hz, 2H), 3.82 (t, J=7.5 Hz, 1H), 3.22 (t, J=9.8 Hz, 1H), 3.03 (dd,J=7.0, 2.3 Hz, 1H), 1.36 (t, J=7.1 Hz, 3H), 1.08 (s, 9H); MS (APCI+) m/z399 (M+H)⁺.

Core 11 (2S,3R,4S,5S)-tert-butyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-2-carboxylateCore 11A (E)-tert-butyl 2-((2-isopropylbenzylidene)amino)acetate

To a stirred suspension of tert-butyl 2-aminoacetate hydrochloride (2.55g, 14.74 mmol) and magnesium sulfate (3.55 g, 29.5 mmol) in anhydrousCH₂Cl₂ (50 mL) at room temperature was slowly added triethylamine (2.158mL, 15.48 mmol). The mixture was stirred for 15 minutes, treated with2-isopropylbenzaldehyde (2.3 g, 14.74 mmol), and stirred overnight. Thesolid material was removed via filtration and the filtrate was washedwith water (quick wash twice) and brine, then dried over sodium sulfate,filtered and concentrated to provide (E)-tert-butyl2-((2-isopropylbenzylidene)amino)acetate (3.85 g, 14.74 mmol, 100%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.68 (s, 1H), 7.75 (dd, J=7.8,1.4 Hz, 1H), 7.44-7.32 (m, 2H), 7.21 (ddd, J=8.1, 7.0, 1.7 Hz, 1H), 4.30(d, J=1.2 Hz, 2H), 3.58 (hept, J=6.8 Hz, 1H), 1.40 (s, 9H), 1.24-1.15(m, 6H). MS (DCI+) m/z 262.1 (M+H)⁺.

Core 11B (2S,3R,4S,5S)-tert-butyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.075 g, 0.100 mmol) and copper (I) triflate dimer, benzene complex(0.019 g, 0.038 mmol) were dissolved in tetrahydrofuran (11.83 mL) thathad been sparged with an nitrogen stream for 2 hours. The resultingmixture was stirred for 1.5 hours at room temperature, and(E)-tert-butyl 2-((2-isopropylbenzylidene)amino)acetate (2.01 g, 7.69mmol) neat was added after cooling to <5° C. in an ice-water bath.Potassium 2-methylpropan-2-olate (0.077 mL, 0.077 mmol) was added dropwise, followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene (0.993g, 7.69 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete, the reaction mixturewas stirred for 15 minutes at the same temperature. The reaction mixturewas diluted with methyl tert-butyl ether (60 mL) and stirred with 40 mLof saturated aqueous ammonium chloride at room temperature for 15minutes. The organic layer was separated and washed with saturatedaqueous sodium bicarbonate and brine, dried over sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (0 to 30% ethyl acetate in heptane) to provide(2S,3R,4S,5S)-tert-butyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-2-carboxylate(2.48 g, 6.35 mmol, 83% yield). ¹H NMR (501 MHz, DMSO-d₆) δ ppm 7.35(dd, J=7.9, 1.4 Hz, 1H), 7.31-7.18 (m, 2H), 7.10 (ddd, J=8.5, 7.3, 1.5Hz, 1H), 5.08 (dd, J=7.0, 3.6 Hz, 1H), 4.70 (dd, J=8.5, 6.9 Hz, 1H),3.61 (t, J=7.7 Hz, 1H), 3.40 (t, J=8.1 Hz, 1H), 3.10 (hept, J=6.8 Hz,1H), 3.00 (dd, J=7.8, 3.5 Hz, 1H), 1.47 (s, 9H), 1.28 (d, J=6.8 Hz, 3H),1.16 (d, J=6.7 Hz, 3H), 0.95 (s, 9H). MS (ESI⁺) m/z 390.9 (M+H)⁺.

Core 12 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-nitropyrrolidine-2-carboxylateCore 12A (E)-ethyl 2-((2-cyclopropylbenzylidene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (4.50 g, 32.2 mmol) and magnesiumsulfate (6.21 g, 51.6 mmol) were suspended in dichloromethane (43.0 mL)and the suspension was treated with triethylamine (4.49 mL, 32.2 mmol).After 1 hour, 2-cyclopropylbenzaldehyde (3.77 g, 25.8 mmol) in 5 mL ofdichloromethane was added and the reaction was stirred at roomtemperature for 16 hours. The solid material was removed via filtrationand the filtrate was washed with water and brine, dried over sodiumsulfate, filtered, and concentrated to provide (E)-ethyl2-((2-cyclopropylbenzylidene)amino)acetate (5.68 g, 24.56 mmol, 95%yield), which was used in the next step without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.92 (d, J=1.5 Hz, 1H), 7.81 (dd, J=7.8,1.5 Hz, 1H), 7.35 (td, J=7.6, 1.5 Hz, 1H), 7.22 (td, J=7.6, 1.2 Hz, 1H),7.05 (dd, J=7.8, 1.2 Hz, 1H), 4.45 (d, J=1.3 Hz, 2H), 4.13 (q, J=7.1 Hz,2H), 2.33 (tt, J=8.5, 5.3 Hz, 1H), 1.21 (t, J=7.1 Hz, 3H), 1.03-0.90 (m,2H), 0.75-0.63 (m, 2H). MS (ESI⁺) m/z 232.1 (M+H)⁺.

Core 12B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.241 g, 0.319 mmol) and copper (I) triflate dimer, benzene complex(0.062 g, 0.123 mmol) were dissolved in tetrahydrofuran (63.0 mL) thathad been sparged with an nitrogen stream for 2 hours. The resultingmixture was stirred for 1.5 hours at room temperature, and (E)-ethyl2-((2-cyclopropylbenzylidene)amino)acetate (5.68 g, 24.56 mmol) intetrahydrofuran (8 mL) was added after cooling to <5° C. in an ice-waterbath. Potassium 2-methylpropan-2-olate (0.246 mL, 0.246 mmol) was addeddrop wise, followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene(3.17 g, 24.56 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete, the reaction wasstirred for 15 minutes at the same temperature, diluted with methyltert-butyl ether (100 mL) and stirred with 75 mL of saturated ammoniumchloride at room temperature for 15 minutes. The organic layer wasseparated, washed with saturated sodium bicarbonate and brine, driedover sodium sulfate, and filtered. The filtrate was concentrated andpurified by flash chromatography (0 to 30% ethyl acetate in heptane) toprovide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-nitropyrrolidine-2-carboxylate(6.85 g, 19.00 mmol, 77% yield). ee>97%. ¹H NMR (501 MHz, DMSO-d₆) δ ppm7.34 (dd, J=7.6, 1.5 Hz, 1H), 7.15 (dtd, J=25.3, 7.5, 1.6 Hz, 2H),7.07-7.01 (m, 1H), 5.31 (dd, J=6.7, 3.1 Hz, 1H), 4.92 (dd, J=8.4, 6.6Hz, 1H), 4.27-4.12 (m, 2H), 3.75 (t, J=7.7 Hz, 1H), 3.51 (t, J=8.1 Hz,1H), 3.04 (dd, J=7.6, 3.1 Hz, 1H), 2.06 (tt, J=8.5, 5.4 Hz, 1H), 1.24(t, J=7.1 Hz, 3H), 0.95 (s, 9H), 1.00-0.78 (m, 2H), 0.81-0.68 (m, 1H),0.64-0.55 (m, 1H). MS (ESI⁺) m/z 361.2 (M+H)⁺.

Core 13 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-2-carboxylateCore 13A (E)-ethyl 2-((2-isopropylbenzylidene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (5.02 g, 36.0 mmol) and magnesiumsulfate (5.20 g, 43.2 mmol) were suspended in dichloromethane (45 mL)and treated with triethylamine (9.9 mL, 71.0 mmol). The mixture wasstirred for 20 minutes and was treated dropwise with2-isopropylbenzaldehyde (5 g, 33.7 mmol). The reaction mixture stirredat room temperature for 3 days. The mixture was filtered (fritted glassfunnel), and the filter pad was washed with copious amount of CH₂Cl₂.The filtrates were washed twice with water and once with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to yield the titlecompound, 7.066 g (90% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.73 (m,1H), 7.94 (dd, J=7.9, 1.5 Hz, 1H), 7.42 (m, 1H), 7.35 (dd, J=7.9, 1.4Hz, 1H), 7.24 (m, 1H), 4.44 (d, J=1.4 Hz, 2H), 4.26 (q, J=7.1 Hz, 2H),3.53 (hept, J=6.8 Hz, 1H), 1.34-1.29 (m, 9H). MS (ESI⁺) m/z 234.1(M+H)⁺.

Core 13B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-2-carboxylate

Tetrahydrofuran (30 mL) was sparged with nitrogen for 75 minutes, thenit was treated with copper(I) triflate dimer, benzene complex (0.033 g,0.065 mmol) and(2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.098 g, 0.129 mmol). The mixture was stirred at room temperature for 1hour. The mixture was cooled to <5° C. and treated dropwise with asolution of the product of Step 13A (4.15 g, 17.80 mmol) in 8 mLtetrahydrofuran, followed by dropwise addition of potassium2-methylpropan-2-olate (1M in tetrahydrofuran; 0.1 mL, 0.100 mmol),keeping the temperature<5° C. Neat (E)-3,3-dimethyl-1-nitrobut-1-ene(2.09 g, 16.18 mmol) was then added dropwise over about 10 minutes tokeep the temperature<10° C. After completion of the addition, thereaction continued to stir in the ice bath for 25 minutes. The reactionmixture was then quenched with 25 mL of saturated aqueous NH₄Cl solutionand warmed up to room temperature. The mixture was diluted with methyltert-butyl ether and washed twice with saturated aqueous NH₄Cl solutionand once with brine. The organic layer was dried over Na₂SO₄, filtered,and concentrated in vacuo. Silica gel chromatography, eluting with 10 to50% ethyl acetate-heptanes, afforded the title compound, 1.902 g, (32%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.42-7.34 (m, 1H), 7.30-7.17 (m,2H), 7.08 (ddd, J=7.5, 6.9, 1.7 Hz, 1H), 5.08 (dd, J=6.9, 3.6 Hz, 1H),4.77 (d, J=6.9 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.77 (d, J=7.6 Hz, 1H),3.25 (br s, 1H), 3.21-3.06 (m, 2H), 1.33-1.14 (m, 9H), 0.98 (s, 9H). MS(ESI⁺) m/z 363.1 (M+H)⁺.

Core 14 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-chlorophenyl)-4-nitropyrrolidine-2-carboxylate Core14A (E)-ethyl 2-((2-chlorobenzylidene)amino)acetate

A mixture of ethyl 2-aminoacetate hydrochloride (1.85 g, 13.25 mmol) andmagnesium sulfate (3.19 g, 26.5 mmol) in dichloromethane (22.09 mL)(anhydrous) was treated with triethylamine (1.847 mL, 13.25 mmol),stirred for 30 minutes, and treated with the 2-chlorobenzaldehyde (1.86g, 13.25 mmol) as a solution in 3 mL of dichloromethane. The reactionwas stirred at ambient temperature overnight. The solid material wasfiltered and the filtrate was concentrated. Toluene (5 mL) was added,the mixture was filtered again and concentrated, giving (E)-ethyl2-((2-chlorobenzylidene)amino)acetate (2.76 g, 12.23 mmol, 92% yield)which was used directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ ppm8.77 (d, J=1.5 Hz, 1H), 8.19-8.04 (m, 1H), 7.45-7.39 (m, 2H), 7.34 (ddd,J=8.3, 6.0, 2.6 Hz, 1H), 4.48 (d, J=1.5 Hz, 2H), 4.28 (q, J=7.2 Hz, 2H),1.34 (t, J=7.1 Hz, 3H).

Core 14B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-chlorophenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.175 g, 0.232 mmol) and copper (I) triflate dimer, benzene complex(0.047 g, 0.093 mmol) were dissolved in tetrahydrofuran (19.36 mL mL)that had been sparged with an N₂ stream for 1 hour. The resultingmixture was stirred for 1 hour at ambient temperature (continue nitrogensparge), and (E)-ethyl 2-((2-chlorobenzylidene)amino)acetate (2.75 g,12.19 mmol) was added as a solution in 2 mL of tetrahydrofuran and theresulting solution was cooled to <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate in tetrahydrofuran (0.209 mL, 0.209 mmol) wasadded dropwise, followed by addition of neat(E)-3,3-dimethyl-1-nitrobut-1-ene (1.5 g, 11.61 mmol) over 20 minutes,maintaining a temperature less than 7° C. The reaction mixture wasstirred for 1 hour at 0° C. and quenched with 60 mL of saturated aqueousammonium chloride and 100 mL of ethyl acetate and warmed to ambienttemperature. The organic layer was separated and washed with saturatedaqueous ammonium chloride (2×50 mL) and brine and filtered through a padof silica gel. The organic layer was concentrated. Heptane (70 mL) wasadded, and the resulting precipitate was filtered. The filtrate waspurified by chromatography using a 40 g silica gel cartridge elutingwith a gradient of 0-60% heptanes/ethyl acetate over a period of 20minutes to provide additional product (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-chlorophenyl)-4-nitropyrrolidine-2-carboxylate (2.85g, 8.03 mmol, 69.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.56-7.48(m, 1H), 7.45-7.38 (m, 1H), 7.35-7.24 (m, 2H), 5.25 (dd, J=6.7, 3.0 Hz,1H), 4.71 (t, J=7.0 Hz, 1H), 4.19 (qq, J=7.3, 3.7 Hz, 2H), 3.78 (t,J=7.3 Hz, 1H), 3.68 (t, J=7.3 Hz, 1H), 3.07 (dd, J=7.4, 3.0 Hz, 1H),1.24 (t, J=7.1 Hz, 3H), 0.94 (s, 9H), 0.96 (s, 9H); MS (APCI+) m/z 355(M+H)⁺.

Core 15 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxyphenyl)-4-nitropyrrolidine-2-carboxylateCore 15A (E)-ethyl 2-((2-isopropoxybenzylidene)amino)acetate

To ethyl 2-aminoacetate hydrochloric acid (CAS#623-33-6) (4.68 g, 33.5mmol) and magnesium sulfate (4.03 g, 33.5 mmol) in dichloromethane (80ml) was added triethylamine (4.67 mL, 33.5 mmol). The mixture wasstirred at ambient temperature for 5 minutes, and2-isopropoxybenzaldehyde [CAS#22921-58-0] (5 g, 30.5 mmol) was addeddropwise and stirred overnight. The solid was filtered and the solid waswashed with dichloromethane (10 mL×2). The combined organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated toprovide the title compound, 7.28 g (96% yield). ¹H NMR (501 MHz,Chloroform-d) δ ppm 8.74 (d, J=1.5 Hz, 1H), 8.04 (dd, J=7.8, 1.8 Hz,1H), 7.38 (ddd, J=8.4, 7.3, 1.8 Hz, 1H), 7.00-6.95 (m, 1H), 6.95-6.91(m, 1H), 4.66-4.60 (m, 1H), 4.42 (d, J=1.4 Hz, 2H), 4.26 (q, J=7.1 Hz,2H), 1.38 (d, J=6.1 Hz, 6H), 1.32 (t, J=7.1 Hz, 3H).

Core 15B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxyphenyl)-4-nitropyrrolidine-2-carboxylate

A mixture of(2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.109 g, 0.144 mmol) and copper(I) triflate dimer, benzene complex(0.030 g, 0.060 mmol) in tetrahydrofuran (40 mL) cooled in an ice-bathwas sparged with N₂ for 1 hour. Example 15A (7 g, 28.1 mmol) in 10 mLtetrahydrofuran was added, followed by potassium 2-methylpropan-2-olate(10.80 mg, 0.096 mmol), and (E)-3,3-dimethyl-1-nitrobut-1-ene (1.632 g,12.64 mmol) dropwise, maintaining an internal temperature<10° C. Themixture was stirred at the same temperature for 2 hours, diluted withethyl acetate (50 mL) and saturated aqueous ammonium chloride (50 mL).The organic layer was washed with saturated aqueous NaHCO₃ and brine,dried over Na₂SO₄, filtered, and concentrated. Purification viachromatography on a 80 g silica gel cartridge, eluting with ethylacetate in heptane at 0-40% gradient provided the title compound 2.84 g(62.4% yield). ¹H NMR (501 MHz, Chloroform-d) δ ppm 7.29-7.22 (m, 2H),6.93 (td, J=7.6, 1.1 Hz, 1H), 6.87 (dt, J=8.3, 0.7 Hz, 1H), 5.44 (dd,J=5.5, 2.2 Hz, 1H), 4.69 (dtd, J=12.1, 6.0, 0.7 Hz, 1H), 4.54 (s, 1H),4.34 (qd, J=7.1, 2.0 Hz, 2H), 3.81 (s, 1H), 3.45 (s, 1H), 2.87 (dd,J=7.1, 2.2 Hz, 1H), 1.48 (d, J=6.0 Hz, 3H), 1.41-1.34 (m, 6H), 1.09 (s,9H); MS (ESI+) m/z 379.1 (M+H)⁺.

Core 16 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidine-2-carboxylateCore 16A (E)-ethyl2-(((2-(trifluoromethyl)pyridin-3-yl)methylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (3.49 g, 24.98 mmol) and magnesiumsulfate (4.81 g, 40.0 mmol) were suspended in dichloromethane (33.3 mL)and the suspension was treated with triethylamine (3.48 mL, 24.98 mmol).After 1 hour, 2-(trifluoromethyl)nicotinaldehyde (3.5 g, 19.99 mmol) indichloromethane (5 mL) was added and the reaction mixture was stirred atroom temperature for 16 hours. The solid material was removed viafiltration and the filtrate was washed with water and brine, dried oversodium sulfate, filtered, and concentrated to provide (E)-ethyl2-(((2-(trifluoromethyl)pyridin-3-yl)methylene)amino)acetate (5.08 g,19.52 mmol, 98% yield), which was used without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.80 (dd, J=4.6, 1.6 Hz, 1H), 8.68 (td,J=2.5, 1.4 Hz, 1H), 8.62-8.45 (m, 1H), 7.87-7.62 (m, 1H), 4.56 (d, J=1.3Hz, 2H), 4.13 (m, 2H), 1.19 (m, 3H). MS (ESI⁺) m/z 261.0 (M+H)⁺.

Core 16B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidine-2-carboxylate

To a 250 mL flask was added tetrahydrofuran (50 mL). The mixture wassparged with a nitrogen stream for 2 hours, and(2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.191 g, 0.254 mmol), and copper (I) triflate dimer, benzene complex(0.049 g, 0.098 mmol) were added. The reaction mixture was sparged witha nitrogen stream for 90 minutes at room temperature, and (E)-ethyl2-(((2-(trifluoromethyl)pyridin-3-yl)methylene)amino)acetate (5.08 g,19.52 mmol) in tetrahydrofuran (8 mL) was added after cooling to <5° C.in an ice-water bath. Potassium 2-methylpropan-2-olate (0.195 mL, 0.195mmol) was added drop wise, followed by addition of(E)-3,3-dimethyl-1-nitrobut-1-ene (2.52 g, 19.52 mmol) neat over 25minutes, maintaining an internal temperature<10° C. After the additionwas complete, the reaction mixture was stirred for 15 minutes, dilutedwith methyl tert-butyl ether (100 mL), and stirred with 75 mL ofsaturated aqueous ammonium chloride at room temperature for 15 minutes.The organic layer was separated and washed with saturated aqueous sodiumbicarbonate and brine, then dried over sodium sulfate. The mixture wasfiltered, concentrated and purified by flash chromatography (0 to 30%ethyl acetate in heptane) to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidine-2-carboxylate(4.56 g, 11.71 mmol, 60.0% yield). ee=95.4%. ¹H NMR (501 MHz, DMSO-d₆) δppm 8.65 (m, 1H), 8.27 (dd, J=8.1, 1.5 Hz, 1H), 7.72 (ddd, J=19.7, 8.0,4.6 Hz, 1H), 5.02 (dd, J=7.1, 3.3 Hz, 1H), 4.84 (t, J=6.5 Hz, 1H), 4.20(qq, J=7.0, 3.7 Hz, 2H), 3.94 (t, J=5.9 Hz, 1H), 3.83 (dd, J=7.3, 6.3Hz, 1H), 3.19 (dd, J=7.4, 3.3 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.93 (s,9H). MS (ESI⁺) m/z 390.1 (M+H)⁺.

Core 17 (2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-2-carboxylate Core17A (E)-ethyl 2-((3-bromobenzylidene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (2.490 g, 17.84 mmol) and magnesiumsulfate (2.147 g, 17.84 mmol) were stirred in dichloromethane (24.13 mL)at ambient temperature, and triethylamine (2.486 mL, 17.84 mmol) wasadded. The mixture was stirred for 5 minutes and 3-bromobenzaldehyde(1.890 mL, 16.21 mmol) was added dropwise. The mixture was stirred atambient temperature for 16 hours. The solid material was filteredthrough a disposable plastic frit and washed with dichloromethane. Theorganic layer was washed with 30 mL of water, dried over sodium sulfate,filtered, then concentrated to provide (E)-ethyl2-((3-bromobenzylidene)amino)acetate (4.38 g, 16.21 mmol, 100% yield).¹H NMR (500 MHz, CDCl₃) δ ppm 8.27 (d, J=1.4 Hz, 1H), 8.01 (t, J=1.8 Hz,1H), 7.70 (dt, J=7.7, 1.3 Hz, 1H), 7.61 (ddd, J=8.0, 2.0, 1.0 Hz, 1H),7.33 (t, J=7.8 Hz, 1H), 4.44 (d, J=1.3 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H),1.35 (t, J=7.1 Hz, 3H); MS (ESI+) m/z 224 (M+H)⁺.

Core 17B (2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.139 g, 0.184 mmol) and copper (I) triflate dimer, benzene complex(0.040 g, 0.079 mmol) were dissolved in tetrahydrofuran (32.4 mL) thathad been sparged with a nitrogen stream for 1 hour. The resultingmixture was stirred for 1.5 hours at ambient temperature, and (E)-ethyl2-((3-bromobenzylidene)amino)acetate (4.38 g, 16.21 mmol) was addedafter cooling to <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate (0.127 mL, 0.127 mmol) was added dropwise,followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene (2.199 g,17.03 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete, the mixture wasstirred for 2 hours. Additional potassium 2-methylpropan-2-olate (0.127mL, 0.127 mmol) was added. After 30 minutes, the reaction mixture wasdiluted with methyl tert-butyl ether (150 mL) and stirred with 50 mL ofsaturated aqueous ammonium chloride at ambient temperature for 15minutes. The layers were separated. The organic layer was washed withsaturated aqueous sodium bicarbonate and brine, dried over sodiumsulfate, filtered, and concentrated to provide a crude material, whichwas triturated with 3×5 mL of heptanes. The heptane insolubles werechromatographed using an 80 g silica gel cartridge with a gradient of5-50% ethyl acetate/heptanes over 40 minutes to provide(2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-2-carboxylate (2.76g, 6.91 mmol, 42.6% yield). n-Hexane (about 1 mL) was added to about 50mg of the crude material, and the mixture was warmed to 45° C. Themixture was cooled to provide the title compound. Relative and absolutestereochemistry were confirmed by X-ray analysis. ¹H NMR (501 MHz,CDCl₃) δ ppm 7.50 (d, J=1.9 Hz, 1H), 7.45 (dt, J=7.5, 1.7 Hz, 1H),7.29-7.19 (m, 2H), 5.13 (dd, J=6.0, 2.6 Hz, 1H), 4.41 (dd, J=11.9, 6.0Hz, 1H), 4.33 (qd, J=7.1, 1.1 Hz, 2H), 3.81 (dd, J=9.5, 7.2 Hz, 1H),3.27-3.17 (m, 1H), 2.98 (dd, J=7.2, 2.5 Hz, 1H), 1.37 (t, J=7.2 Hz, 3H),1.07 (s, 9H); MS (APCI+) m/z 399 (M+H)⁺.

Core 18 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-nitropyrrolidine-2-carboxylateCore 18A (E)-ethyl 2-((3-(tert-butyl)benzylidene)amino)acetate

To ethyl 2-aminoacetate, hydrochloric acid (CAS#623-33-6, 776 mg, 5.56mmol) and magnesium sulfate (669 mg, 5.56 mmol) in CH₂Cl₂ (10 mL) wasadded triethylamine (0.775 mL, 5.56 mmol). The mixture was stirred atambient temperature for 5 minutes, 3-(tert-butyl)benzaldehyde (820 mg,5.05 mmol) was added dropwise, and the mixture was stirred overnight.The mixture was filtered and the solid was washed with CH₂Cl₂ (10 mL×2).The combined organics were washed with water and brine, dried overMgSO₄, filtered, and concentrated to provide (E)-ethyl2-((3-(tert-butyl)benzylidene)amino)acetate (1.08 g, 86% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.31 (s, 1H), 7.81 (t, J=1.9 Hz, 1H), 7.60 (dt,J=7.5, 1.4 Hz, 1H), 7.50 (ddd, J=7.8, 2.1, 1.2 Hz, 1H), 7.37 (t, J=7.7Hz, 1H), 4.41 (d, J=1.2 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 1.36 (s, 9H),1.32 (t, J=7.1 Hz, 3H).

Core 18B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-nitropyrrolidine-2-carboxylate

A mixture of(2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(37 mg, 0.049 mmol) and copper(I) triflate dimer, benzene complex(CAS#42152-46-5, 10.18 mg, 0.020 mmol) in tetrahydrofuran (10 mL) wasspurred with N₂ for one hour, and Core 18A (1 g, 4.04 mmol) intetrahydrofuran (5 mL) was added at 0° C., followed by addition ofpotassium 2-methylpropan-2-olate (3.63 mg, 0.032 mmol) dropwise, andfinally (E)-3,3-dimethyl-1-nitrobut-1-ene (548 mg, 4.25 mmol)maintaining an internal temperature<10° C. The mixture was stirred atthe same temperature for one hour, diluted with ethyl acetate (20 mL)and saturated aqueous ammonium chloride (20 mL) and stirred at ambienttemperature for 30 minutes. The organic layer washed with NaHCO₃ andbrine, dried over Na₂SO₄, filtered, and concentrated to provide titlecompound which was used in next step without purification. LC/MS (APCI+)m/z 377 (M+1)⁺.

Core 19 (2S,3R,4S,5R)-ethyl3-(tert-butyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-4-nitropyrrolidine-2-carboxylateCore 19A (E)-ethyl2-(((1-isopropyl-1H-pyrazol-5-yl)methylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (2.223 g, 15.92 mmol) and magnesiumsulfate (1.917 g, 15.92 mmol) were stirred in dichloromethane (24.13 mL)at ambient temperature, and triethylamine (2.185 mL, 15.67 mmol) wasadded. The mixture was stirred for 5 minutes and1-isopropyl-1H-pyrazole-5-carbaldehyde (2.0 g, 14.48 mmol) was addeddropwise. The mixture was stirred at ambient temperature for 16 hours.The solid material was filtered through a disposable plastic frit andwashed with dichloromethane. The organic layer was washed with 30 mL ofwater, dried over sodium sulfate, filtered, and concentrated to provide(E)-ethyl 2-(((1-isopropyl-1H-pyrazol-5-yl)methylene)amino)acetate (3.23g, 14.47 mmol, 100% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.29 (t, J=1.3Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.48 (p, J=6.6Hz, 1H), 4.38 (d, J=1.3 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H), 1.50 (d, J=6.6Hz, 6H), 1.31 (t, J=7.1 Hz, 3H); MS (ESI+) m/z 224 (M+H)⁺.

Core 19B (2S,3R,4S,5R)-ethyl3-(tert-butyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.124 g, 0.164 mmol) and copper (I) triflate dimer, benzene complex(0.036 g, 0.071 mmol) were dissolved in tetrahydrofuran (28.9 mL) thathad been sparged with a nitrogen stream for 1 hour. The resultingmixture was stirred for 1.5 hours at ambient temperature, and (E)-ethyl2-(((1-isopropyl-1H-pyrazol-5-yl)methylene)amino)acetate (3.23 g, 14.47mmol) was added after cooling to <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate (0.113 mL, 0.113 mmol) was added dropwise,followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene (1.962 g,15.19 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete the reaction wasstirred for 2 hours. The mixture was diluted with methyl tert-butylether (150 mL) and stirred with 50 mL of saturated aqueous ammoniumchloride at ambient temperature for 15 minutes. The layers wereseparated, and the organic layer was washed with saturated sodiumbicarbonate and brine, and dried over sodium sulfate. After filtration,the combined organic layers were concentrated and triturated with 3×5 mLof heptanes and left in dry ice overnight in heptanes. The solvent wasremoved and the resulting material concentrated. n-Hexane was added andthe mixture was triturated and stirred at ambient temperature for anhour. The mixture was filtered and washed with 10 mL of heptanes toprovide (2S,3R,4S,5R)-ethyl3-(tert-butyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-4-nitropyrrolidine-2-carboxylate(2.556 g, 7.25 mmol, 50.1% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.50(d, J=1.9 Hz, 1H), 6.21 (d, J=1.9 Hz, 1H), 5.04 (dd, J=5.9, 2.3 Hz, 1H),4.47 (ddd, J=21.6, 12.9, 6.2 Hz, 2H), 4.35 (qd, J=7.2, 1.8 Hz, 2H), 3.82(dd, J=9.4, 6.6 Hz, 1H), 3.30 (dd, J=12.3, 9.5 Hz, 1H), 3.02 (dd, J=6.7,2.3 Hz, 1H), 1.60 (d, J=6.6 Hz, 3H), 1.56 (d, J=6.5 Hz, 3H), 1.37 (t,J=7.1 Hz, 3H), 1.10 (s, 9H); MS (APCI+) m/z 353 (M+H)⁺. Absolutechemistry confirmed by X-ray diffraction analysis.

Core 20 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-methoxypyridin-3-yl)-4-nitropyrrolidine-2-carboxylateCore 20A (E)-ethyl 2-(((2-methoxypyridin-3-yl)methylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (14.50 g, 104 mmol) and magnesiumsulfate (20.01 g, 166 mmol) were suspended in 130 mL of dichloromethane.A solution of 2-methoxynicotinaldehyde (11.4 g, 83 mmol) in 9 mL ofdichloromethane was added to the stirring mixture, followed by additionof triethylamine (14.48 mL, 104 mmol) and the reaction mixture wasstirred for 16 hours at ambient temperature. The solid material wasremoved via filtration and the filtrate was washed quickly with coldwater (2×10 mL) and brine (10 mL) and dried over sodium sulfate,filtered, and concentrated to provide the crude imine, which was usedwithout additional purification. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.58(d, J=1.6 Hz, 1H), 8.31 (dd, J=4.9, 2.0 Hz, 1H), 8.19 (dd, J=7.4, 2.0Hz, 1H), 7.09 (ddd, J=7.4, 4.9, 0.7 Hz, 1H), 4.45 (d, J=1.4 Hz, 2H),4.14 (q, J=7.2 Hz, 2H), 3.96 (s, 3H), 1.22 (t, J=7.1 Hz, 3H).

Core 20B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-methoxypyridin-3-yl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.642 g, 0.853 mmol) and copper (I) triflate dimer, benzene complex(0.185 g, 0.367 mmol) were dissolved in tetrahydrofuran (150 mL) thathad been sparged with an N₂ stream for 4 hours. The resulting mixturewas stirred for 1.5 hours ambient temperature, and (E)-ethyl2-(((2-methoxypyridin-3-yl)methylene)amino)acetate (17.50 g, 79 mmol)was then added via syringe after cooling the flask to an internaltemperature of <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate (0.588 mL, 0.588 mmol) was added dropwise viasyringe, followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene (9.69g, 75.0 mmol) neat via syringe over 25 minutes, maintaining an internaltemperature<10° C. The reaction mixture was stirred for an additional 20minutes at the same temperature, at which point LC-MS indicated completeconsumption of the nitroalkene. The reaction mixture was diluted withmethyl tert-butyl ether (300 mL) and stirred with 300 mL of saturatedaqueous ammonium chloride at ambient temperature for 15 minutes. Thelayers were separated and the organic layer was washed with saturatedsodium bicarbonate and brine, dried over sodium sulfate, filtered andconcentrated. The crude material was purified via silica gelchromatography, eluting with 0:100 to 50:50 ethyl acetate:heptanes over30 minutes on a 330 g column to provide 17.5 g of the title compound. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.13 (dd, J=5.0, 1.5 Hz, 1H), 7.62-7.34 (m,1H), 6.96-6.71 (m, 1H), 5.36 (dt, J=5.7, 1.8 Hz, 1H), 4.54-4.38 (m, 1H),4.41-4.25 (m, 2H), 4.04 (s, 3H), 3.82-3.65 (m, 1H), 3.28 (s, 1H), 2.93(dt, J=7.3, 1.8 Hz, 1H), 1.37 (td, J=7.2, 1.2 Hz, 3H), 1.08 (s, 9H).MS(ESI+) m/z 352.1 (M+H)⁺.

Core 21 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(2-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylateCore 21A

(E)-ethyl 2-((2-(trifluoromethyl)benzylidene)amino)acetate A slurry ofethyl 2-aminoacetate hydrochloride (6.01 g, 43.1 mmol) and magnesiumsulfate (5.88 g, 48.8 mmol) in dichloromethane (100 mL) was stirred at0° C. Triethylamine (6.00 mL, 43.1 mmol) was added drop wise and themixture was stirred at room temperature for 1 hour.2-(Trifluoromethyl)benzaldehyde (5 g, 28.7 mmol) was added. After 15hours, the solid was filtered and washed with dichloromethane (3×200mL). The dichloromethane layer was washed with water (2×100 mL), dried(Na₂SO₄), filtered, and concentrated, to provide (E)-ethyl2-((2-(trifluoromethyl)benzylidene)amino)acetate (7.2 g, 25.8 mmol, 90%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.64 (s, 1H), 8.28 (d, J=7.6 Hz,1H), 7.61-7.51 (m, 2H), 7.69-7.67 (m, 1H), 4.45 (s, 2H), 4.24 (q, J=6.8Hz, 2H), 1.30 (t, J=7.0 Hz, 3H).

Core 21B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(2-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.169 g, 0.225 mmol) and copper (I) triflate dimer, benzene complex(0.048 g, 0.095 mmol) were added under an argon atmosphere to aflame-dried flask, containing activated 4 Å molecular sieves and astirring bar. The freshly distilled anhydrous tetrahydrofuran (20 mL)was added. After being stirred for 15 minutes, the solution was cooledto 0° C. before (E)-ethyl2-((2-(trifluoromethyl)benzylidene)amino)acetate (2.408 g, 9.29 mmol)was added, followed by potassium tert-butoxide (0.155 mL, 0.155 mmol).(E)-3,3-Dimethyl-1-nitrobut-1-ene (1 g, 7.74 mmol) was added slowly. Thereaction mixture was stirred at 0° C. for 5 hours, and water (80 mL) wasadded to the flask. The aqueous layer was extracted with ethyl acetate(2×100 mL). The organic layers were combined, washed with brine (2×80mL), dried over Na₂SO₄, filtered, and concentrated. The crude materialwas purified by chromatography on silica gel (ethyl acetate/petroleummixture 1:40) to provide title compound (2 g, 5.10 mmol, 65.8% yield).¹H NMR (400 MHz, CDCl₃) δ ppm 7.69-7.41 (m, 4H), 5.07-5.06 (m, 1H),4.81-4.78 (m, 1H), 4.32 (q, 2H), 3.82 (t, J=7.2 Hz, 1H), 3.15-3.13 (m,1H), 3.01 (t, J=8.6 Hz, 1H), 1.34 (t, J=7.2 Hz, 3H), 1.03 (s, 9H).

Core 22 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-(difluoromethyl)phenyl)-4-nitropyrrolidine-2-carboxylateCore 22A (E)-ethyl 2-((2-(difluoromethyl)benzylidene)amino)acetate

A mixture of ethyl 2-aminoacetate hydrochloride (1.788 g, 12.81 mmol)and magnesium sulfate (3.08 g, 25.6 mmol) in dichloromethane (21.35 mL)(anhydrous) was treated with triethylamine (1.785 mL, 12.81 mmol),stirred for 10 minutes and treated with 2-(difluoromethyl)benzaldehyde(2.00 g, 12.81 mmol) as a solution in 4 mL of dichloromethane. Themixture was stirred at ambient temperature overnight. The solid materialwas filtered, the filtrate was concentrated, toluene (25 mL) was added,and the mixture was filtered again. The mixture was concentrated toprovide (E)-ethyl 2-((2-(difluoromethyl)benzylidene)amino)acetate (3.0g, 12.44 mmol, 97% yield) which was used directly on to the next step.¹H NMR (400 MHz, CDCl₃) δ ppm 8.59 (t, J=1.4 Hz, 1H), 8.00-7.87 (m, 1H),7.70 (dd, J=6.6, 2.3 Hz, 1H), 7.63-7.52 (m, 2H), 7.35 (t, J=55.1 Hz,1H), 4.47 (d, J=1.3 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz,3H).

Core 22B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-(difluoromethyl)phenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.187 g, 0.249 mmol) and copper (I) triflate dimer, benzene complex(0.050 g, 0.099 mmol) were dissolved in tetrahydrofuran (12.9 mL) thathad been sparged with an N₂ stream for 1 hour. The resulting mixture wasstirred for 1 hour at ambient temperature (continue nitrogen sparge),and (E)-ethyl 2-((2-(difluoromethyl)benzylidene)amino)acetate (3.0 g,12.44 mmol) was added as a solution in 1.5 mL of tetrahydrofuran and theresulting solution was cooled to <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate in tetrahydrofuran (0.224 mL, 0.224 mmol) wasadded dropwise, followed by addition of neat(E)-3,3-dimethyl-1-nitrobut-1-ene (1.606 g, 12.44 mmol) over 2 minutes,maintaining a temperature less than 7° C. The reaction mixture wasstirred for 3 hours at 0° C. The mixture was quenched with 10 mL ofsaturated aqueous ammonium chloride and 30 mL of ethyl acetate and itwas warmed to ambient temperature. The organic layer was separated andwashed with saturated aqueous ammonium chloride (2×20 mL) and brine andfiltered through a pad of silica gel. The filtrate was concentrated. Theresidue was triturated with heptane, decanted, precipitated in hotheptane, and filtered to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-(difluoromethyl)phenyl)-4-nitropyrrolidine-2-carboxylate(2.48 g, 6.70 mmol, 53.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64(d, J=7.7 Hz, 1H), 7.57-7.53 (m, 1H), 7.48 (t, J=7.4 Hz, 1H), 7.45-7.39(m, 1H), 7.38 (t, J=54.4 Hz, 1H), 5.19 (dd, J=7.0, 3.4 Hz, 1H), 4.79 (t,J=6.5 Hz, 1H), 4.19 (qd, J=7.1, 2.4 Hz, 2H), 3.83-3.61 (m, 2H), 3.11(dd, J=6.9, 3.5 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H), 0.93 (s, 9H); MS (ESI+)m/z 371 (M+H)⁺.

Core 23 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2,6-difluorophenyl)-4-nitropyrrolidine-2-carboxylateCore 23A (E)-ethyl 2-((2,6-difluorobenzylidene)amino)acetate

A mixture of ethyl 2-aminoacetate hydrochloride (1.85 g, 13.25 mmol) andmagnesium sulfate (3.19 g, 26.5 mmol) in dichloromethane (22.09 mL)(anhydrous) was treated with triethylamine (1.847 mL, 13.25 mmol),stirred for 30 minutes and treated with 2,6-difluorobenzaldehyde (1.88g, 13.25 mmol) as a solution in 3 mL of dichloromethane. The vial wascapped and stirred at ambient temperature overnight. The solid materialwas filtered. The filtrate was concentrated, toluene (5 mL) was added,and the mixture was filtered again and concentrated, to provide(E)-ethyl 2-((2,6-difluorobenzylidene)amino)acetate (2.9 g, 12.76 mmol,96% yield) which was used directly in the next step. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.54 (d, J=1.3 Hz, 1H), 7.13-6.81 (m, 3H), 4.49 (s, 2H),4.28 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).

Core 23B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2,6-difluorophenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.175 g, 0.232 mmol) and copper (I) triflate dimer, benzene complex(0.047 g, 0.093 mmol) were dissolved in tetrahydrofuran (19.36 mL mL)that had been sparged with an N₂ stream for 1 hour. The resultingmixture was stirred for 1 hour at ambient temperature (continue nitrogensparge), and (E)-ethyl 2-((2,6-difluorobenzylidene)amino)acetate (2.9 g,12.76 mmol) was added as a solution in 2 mL of tetrahydrofuran. Theresulting solution was cooled to <5° C. in an ice-water bath. Potassium2-methylpropan-2-olate in tetrahydrofuran (0.244 mL, 0.244 mmol) wasadded dropwise, followed by addition of(E)-3,3-dimethyl-1-nitrobut-1-ene (1.5 g, 11.61 mmol) in 2 mLtetrahydrofuran over 2 minutes, maintaining a temperature less than 7°C. The reaction mixture was stirred for 1 hour at 0° C. The mixture wasquenched with 4 mL of saturated aqueous ammonium chloride and 10 mL ofdiethyl ether and warmed to ambient temperature. The ether layer wasseparated and washed with saturated aqueous ammonium chloride (2×20 mL)and brine and filtered through a pad of silica gel. The filtrate wasconcentrated, and heptane (60 mL) was added. The precipitate wascollected by filtration and the filtrate was concentrated and purifiedby chromatography using a 24 g silica gel cartridge eluting with agradient of 0-60% heptanes/ethyl acetate over a period of 20 minutes toprovide a combined yield of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2,6-difluorophenyl)-4-nitropyrrolidine-2-carboxylate(1.9 g, 5.33 mmol, 45.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.44(tt, J=8.3, 6.5 Hz, 1H), 7.12 (dd, J=9.5, 8.4 Hz, 2H), 5.21 (dd, J=6.2,3.3 Hz, 1H), 4.67 (dd, J=13.1, 6.2 Hz, 1H), 4.21 (qd, J=7.1, 4.5 Hz,2H), 3.83 (dd, J=13.3, 10.5 Hz, 1H), 3.73 (dd, J=10.7, 7.6 Hz, 1H), 2.88(dd, J=7.6, 3.3 Hz, 1H), 1.23 (t, J=7.1 Hz, 3H), 0.96 (s, 9H); MS(APCI+) m/z 357 (M+H)⁺.

Core 24 (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitropyrrolidine-2-carboxylate Core24A (E)-ethyl 2-((2-ethylbenzylidene)amino)acetate

A mixture of ethyl 2-aminoacetate hydrochloride (1.85 g, 13.25 mmol) andmagnesium sulfate (3.19 g, 26.5 mmol) in dichloromethane (22 mL)(anhydrous) was treated with triethylamine (1.847 mL, 13.25 mmol),stirred for 10 minutes and treated with 2-ethylbenzaldehyde (1.78 g,13.25 mmol) as a solution in 1 mL of dichloromethane. The flask wascapped and stirred at ambient temperature overnight. The solid materialwas filtered, the filtrate was washed with water, and the organic layerwas dried with Na₂SO₄ and filtered again. The filtrate was concentrated,giving (E)-ethyl 2-((2-ethylbenzylidene)amino)acetate (2.65 g, 12.09mmol, 91% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.63 (s, 1H), 7.96 (dd,J=7.8, 1.5 Hz, 1H), 7.37 (td, J=7.5, 1.5 Hz, 1H), 7.26 (d, J=6.1 Hz,1H), 7.25-7.19 (m, 1H), 4.43 (d, J=1.4 Hz, 2H), 4.26 (q, J=7.1 Hz, 2H),2.89 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H).

Core 24B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.182 g, 0.242 mmol) and copper (I) triflate dimer, benzene complex(0.049 g, 0.097 mmol) were dissolved in tetrahydrofuran (18 mL) that hadbeen sparged with an N₂ stream for 1 hour. The resulting mixture wasstirred for 1 hour at ambient temperature (continued nitrogen sparge),and (E)-ethyl 2-((2-ethylbenzylidene)amino)acetate (2.65 g, 12.09 mmol)in 1 mL tetrahydrofuran was added. The resulting solution was cooled to<5° C. in an ice-water bath. Potassium 2-methylpropan-2-olate intetrahydrofuran (0.218 mL, 0.218 mmol) was added dropwise, followed byaddition of (E)-3,3-dimethyl-1-nitrobut-1-ene (1.561 g, 12.09 mmol) in 1mL tetrahydrofuran over 2 minutes, maintaining a temperature less than7° C. The reaction mixture was stirred for 1.5 hours at 0° C. Themixture was quenched with 20 mL of saturated aqueous ammonium chlorideand 50 mL of ethyl acetate and warmed to ambient temperature. Theorganic layer was separated and washed with saturated aqueous ammoniumchloride (2×50 mL) and brine and filtered through a pad of silica gel.The filtrate was concentrated. The crude material was purified bychromatography using a 40 g silica gel cartridge eluting with a gradientof 0-60% heptanes/ethyl acetate over a period of 20 minutes. The crudematerial was triturated with heptane and the precipitate was filtered toprovide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitropyrrolidine-2-carboxylate (2.11g, 6.06 mmol, 50.1% yield). ¹H NMR (501 MHz, DMSO-d₆) δ ppm 7.40-7.29(m, 1H), 7.25-7.15 (m, 2H), 7.11 (td, J=7.4, 1.8 Hz, 1H), 5.17 (dd,J=7.0, 3.5 Hz, 1H), 4.64 (t, J=7.4 Hz, 1H), 4.19 (qd, J=7.1, 3.8 Hz,2H), 3.72 (t, J=7.6 Hz, 1H), 3.47 (t, J=7.5 Hz, 1H), 3.07 (dd, J=7.9,3.5 Hz, 1H), 2.72 (dt, J=15.0, 7.5 Hz, 1H), 2.63 (dt, J=15.0, 7.5 Hz,1H), 1.22 (dt, J=16.4, 7.3 Hz, 6H), 0.93 (s, 9H); MS (APCI+) m/z 349(M+H)⁺.

Example 1rac-(2R,3S,5R)-3-tert-butyl-1-(cyclopentylacetyl)-4-[(2,5-dichlorophenyl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid Example 1A rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(2-cyclopentylacetyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

To a cooled (ice bath) solution of Core 1 (1.6 g, 4.99 mmol) andtriethylamine (1.047 mL, 7.49 mmol) in dichloromethane (10 mL) wastreated with 2-cyclopentylacetyl chloride (0.436 mL, 3.23 mmol). Thereaction mixture was stirred in an ice-bath for 30 minutes and allowedto warm to ambient temperature. Dichloromethane (20 mL) was added. Theorganics were washed with saturated aqueous NaHCO₃ and brine, dried overMgSO₄, filtered and concentrated. The residue was chromatographed on a40 g silica gel cartridge, eluting with ethyl acetate in heptanes at0-40% gradient to provide title compound, 1.43 g (66.5% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.65 (d, J=6.9 Hz, 2H), 7.38 (d, J=7.2 Hz, 3H),5.52-5.22 (m, 2H), 4.86 (d, J=4.5 Hz, 1H), 4.37 (d, J=8.8 Hz, 2H), 3.14(t, J=3.8 Hz, 1H), 2.52-1.40 (m, 9H), 1.39 (dd, J=11.8, 4.9 Hz, 3H),1.08 (d, J=5.4 Hz, 9H), 0.95-0.84 (m, 2H); MS (ESI+) m/z 431 (M+H)⁺.

Example 1B rac-(2R,3S,5R)-methyl3-(tert-butyl)-1-(2-cyclopentylacetyl)-4-oxo-5-phenylpyrrolidine-2-carboxylate

To potassium dichromate (1.8 g, 6.12 mmol) in 6 M aqueous HCl acid (50mL) was added zinc powder (3.4 g) under a N₂ atmosphere. After thecomplete dissolution of zinc, the formed chromium (II) chloride wastransferred via cannula to the refluxing solution of Example 1A (0.439g, 1.020 mmol) in methanol (50 mL). After 4 hours of refluxing, LC/MSshowed two main peaks, one was desired product and the other wasintermediate oxime. The reaction mixture was cooled and concentrated tohalf of its volume, and extracted with dichloromethane (50 mL×3). Theorganic phase was washed with saturated aqueous NaHCO₃ and brine, driedover MgSO₄, filtered, and concentrated. Purification via chromatographyon a 40 g silica gel cartridge, eluting with ethyl acetate in heptanesat 0-100% gradient, provided two major products, one was the titlecompound 0.12 g (30.5% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.72-7.60(m, 2H), 7.41 (dd, J=8.4, 6.6 Hz, 2H), 7.38-7.30 (m, 1H), 4.95-4.79 (m,2H), 3.83 (s, 3H), 2.57 (d, J=5.2 Hz, 1H), 2.22 (hept, J=7.6 Hz, 1H),2.13-1.96 (m, 2H), 1.73 (ddt, J=38.6, 12.8, 6.3 Hz, 2H), 1.44 (ddtd,J=23.5, 15.7, 8.5, 4.6 Hz, 4H), 1.10 (s, 9H), 0.98-0.86 (m, 2H); MS(ESI+) m/z 386 (M+H)⁺.

Example 1C rac-(2R,3S,5R)-methyl3-(tert-butyl)-1-(2-cyclopentylacetyl)-4-hydroxy-5-phenylpyrrolidine-2-carboxylate

A solution of Example 1B (100 mg, 0.259 mmol) in methanol (6 mL) wascooled to 0° C., treated with sodium borohydride (11.78 mg, 0.311 mmol),stirred at 0° C. for 30 minutes, and warmed to ambient temperature foranother 30 minutes. LC/MS indicated the starting material was consumed.The solvent was removed and the residue was diluted withdichloromethane. The organics were washed with saturated aqueous NaHCO₃and brine, dried over Na₂SO₄, filtered, and concentrated. Purificationvia chromatography on a 12 g silica gel cartridge, eluting with ethylacetate in heptanes at 0-50% gradient provided rac-(2R,3S,5R)-methyl3-(tert-butyl)-1-(2-cyclopentylacetyl)-4-hydroxy-5-phenylpyrrolidine-2-carboxylate(62 mg, 61.7% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.74-7.64 (m, 2H),7.53-7.42 (m, 2H), 7.41-7.34 (m, 1H), 5.03 (d, J=6.4 Hz, 1H), 4.64 (d,J=4.6 Hz, 1H), 4.40 (td, J=6.8, 4.1 Hz, 1H), 3.84 (s, 3H), 2.28 (t,J=4.4 Hz, 1H), 2.19 (h, J=7.8 Hz, 1H), 2.02 (dd, J=15.7, 7.4 Hz, 1H),1.90 (dd, J=15.6, 6.9 Hz, 1H), 1.77 (dq, J=13.0, 6.4 Hz, 1H), 1.68-1.61(m, 1H), 1.60 (s, 1H), 1.51-1.37 (m, 4H), 1.06 (s, 9H), 0.89 (dtt,J=16.1, 7.9, 4.1 Hz, 2H); MS (ESI+) m/z 388 (M+H)⁺.

Example 1Drac-(2R,3S,5R)-3-tert-butyl-1-(cyclopentylacetyl)-4-[(2,5-dichlorophenyl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid

To 2-(bromomethyl)-1,4-dichlorobenzene (33.4 mg, 0.139 mmol) and Example1C (45 mg, 0.116 mmol) in dimethylformamide (1.0 mL) at ambienttemperature was added sodium hydride (6.97 mg, 0.174 mmol) portionwise.The mixture was stirred at 60° C. for 3 hours, and then cooled to roomtemperature. Aqueous LiOH solution (6M, 1.0 mL) was added and thereaction was stirred for another 2 hours. The mixture was adjusted pH to1-2 by adding 2M aqueous HCl and was concentrated. Dichloromethane (2mL) was added and the mixture was filtered through a syringe filter.Purification of the residue via chromatography, eluting with ethylacetate/methanol (95:5) in heptanes in 0-40 gradient providedrac-(2R,3S,5R)-3-(tert-butyl)-1-(2-cyclopentylacetyl)-4-((2,5-dichlorobenzyl)oxy)-5-phenylpyrrolidine-2-carboxylicacid, 19 mg (30.7% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.40-7.26 (m,5H), 7.14-6.99 (m, 2H), 6.51 (d, J=2.4 Hz, 1H), 5.13 (d, J=6.6 Hz, 1H),4.73 (d, J=3.5 Hz, 1H), 4.48 (d, J=13.7 Hz, 1H), 4.18 (dd, J=6.6, 3.3Hz, 1H), 4.10 (d, J=13.7 Hz, 1H), 2.27-1.98 (m, 3H), 1.76 (dt, J=12.6,6.3 Hz, 1H), 1.62 (dq, J=12.3, 6.4 Hz, 1H), 1.55-1.32 (m, 4H), 1.04 (s,9H), 0.99-0.90 (m, 1H), 0.81 (dq, J=12.4, 7.9 Hz, 1H); MS (ESI+) m/z 532(M+H)⁺.

Example 2rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid Example 2A rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

A solution of Core 1 (5.0 g, 15.61 mmol) and triethylamine (3.27 mL,23.41 mmol) in dichloromethane (40 mL) cooling in an ice-bath wastreated with cyclohexanecarbonyl chloride (2.71 mL, 20.29 mmol). Themixture was stirred at 0° C. for 30 minutes and was allowed to warm toroom temperature. Dichloromethane (20 mL) was added. The mixture waswashed with saturated aqueous NaHCO₃ and brine, and dried over MgSO₄,filtered and concentrated. Purification via chromatography on an 80 gsilica gel cartridge eluting with ethyl acetate in heptanes at 0-40%gradient provided the title compound 6.2 g (92% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.64 (d, J=7.1 Hz, 2H), 7.42-7.31 (m, 3H), 5.43 (d, J=9.1Hz, 1H), 5.34 (dd, J=9.0, 4.4 Hz, 1H), 4.79 (d, J=4.6 Hz, 1H), 4.33 (q,J=7.2 Hz, 2H), 3.12 (t, J=4.7 Hz, 1H), 2.03 (dd, J=13.3, 10.0 Hz, 1H),1.85-1.65 (m, 2H), 1.61 (d, J=13.1 Hz, 1H), 1.54-1.38 (m, 4H), 1.35 (d,J=7.2 Hz, 3H), 1.27 (d, J=13.7 Hz, 1H), 1.15 (d, J=14.5 Hz, 1H), 1.04(s, 9H), 0.56 (q, J=13.2 Hz, 1H); MS (ESI+) m/z 431 (M+H).

Example 2B rac-(2R,3S,5R)-methyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-oxo-5-phenylpyrrolidine-2-carboxylate

Potassium dichromate (5.11 g, 17.37 mmol) was dissolved in 6 M aqueousHCl acid (60 mL) and zinc (6 g, 92 mmol) was added under N₂ atmosphere.Complete dissolution of the zinc provided a clear light blue solution.The formed chromium(II) chloride was transferred to a refluxing solutionof Example 2A (1.1 g, 2.55 mmol) in ethanol (60 mL) under N₂. Thereaction mixture was refluxed for 16 hours. LC/MS indicated conversionwas complete and two products were formed, one was desired product andanother was hydrolyzed acid. The mixture was cooled to ambienttemperature and extracted with ethyl acetate (60 mL×3). The organicswere washed with saturated aqueous NaHCO₃ solution and brine, dried overMgSO₄, filtered, and concentrated. The residue was dissolved in ethanol(5 mL), cooled in an ice-bath, and acetyl chloride (1 mL) in ethanol (2mL) was slowly added. The mixture was stirred at 60° C. for 2 hours andLC/MS indicated all acid was converted to the ester. The solvent wasreduced in volume and the crude material was purified via chromatographyon a 80 g silica gel cartridge, eluting with ethyl acetate in heptanesusing a 0-40% gradient to provide the title compound (860 mg, 86%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.68 (dd, J=7.3, 1.7 Hz, 2H),7.45-7.38 (m, 2H), 7.37-7.31 (m, 1H), 4.90 (s, 1H), 4.84 (d, J=5.0 Hz,1H), 4.28 (q, J=7.2 Hz, 2H), 2.54 (dd, J=5.0, 1.0 Hz, 1H), 2.08 (tt,J=11.4, 3.3 Hz, 1H), 1.70 (t, J=14.9 Hz, 2H), 1.54-1.48 (m, 2H),1.47-1.37 (m, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.10 (s, 9H), 0.92-0.82 (m,4H); MS (ESI+) m/z 400.1 (M+H).

Example 2C rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-hydroxy-5-phenylpyrrolidine-2-carboxylate

A solution of Example 2B (200 mg, 0.501 mmol) in methanol (10 mL) wascooled in an ice-bath and was treated with sodium borohydride (37.9 mg,1.001 mmol). The mixture was stirred at 0° C. for 30 minutes, and wasallowed to warm to ambient temperature. The solvent was removed anddichloromethane (20 mL) was added. The mixture was washed with saturatedaqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentratedto provide title compound, 196 mg (98% yield) which used in next stepwithout further purification. LC/MS (APCI+) m/z 402 (M+H)⁺.

Example 2Drac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

To 2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene (40 mg, 0.149mmol) and Example 2C (49.7 mg, 0.124 mmol) in dimethylformamide (1.0 mL)in an ice-bath was added sodium hydride (7.43 mg, 0.186 mmol)portionwise. The mixture was warmed to 60° C. and stirred for 3 hours.Ethyl acetate and water were added. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue wasdissolved in methanol (2 mL) and 6M aqueous LiOH (0.5 mL) and stirred at50° C. overnight. The mixture was adjusted to pH 1˜2 by adding 2Maqueous HCl. The reaction mixture was extracted with ethyl acetate. Theorganic layers were combined, dried over sodium sulfate, andconcentrated. The residue was purified via chromatography, eluting withethyl acetate/methanol (9:1) in heptanes using a 0-40% gradient toprovide the title compound, 22 mg (35% yield). ¹H NMR (400 MHz, CDCl₃) δppm 7.42-7.37 (m, 1H), 7.33 (qd, J=7.7, 6.7, 3.8 Hz, 3H), 7.25-7.20 (m,2H), 6.81-6.75 (m, 2H), 5.17 (d, J=6.6 Hz, 1H), 4.66 (d, J=3.7 Hz, 1H),4.56 (d, J=13.3 Hz, 1H), 4.22-4.11 (m, 2H), 3.77 (s, 3H), 3.15 (t, J=3.5Hz, 1H), 2.35-2.23 (m, 1H), 1.77 (d, J=7.1 Hz, 1H), 1.68 (d, J=13.2 Hz,2H), 1.55-1.41 (m, 2H), 1.40-1.20 (m, 2H), 1.14 (t, J=10.5 Hz, 2H), 1.02(s, 9H), 0.73 (t, J=12.8 Hz, 1H); MS (ESI−) m/z 560 (M−H)⁻.

Example 3rac-(2R,3S,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 2D, substituting 2-(bromomethyl)-4-chloro-1-methoxybenzene for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.40-7.30 (m, 3H), 7.28 (d, J=1.9 Hz, 2H), 7.07 (dd, J=8.6,2.7 Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 6.44 (d, J=2.7 Hz, 1H), 5.14 (d,J=6.6 Hz, 1H), 4.67 (d, J=3.6 Hz, 1H), 4.45 (d, J=13.3 Hz, 1H),4.16-4.10 (m, 2H), 3.70 (s, 3H), 3.08 (t, J=3.5 Hz, 1H), 2.29 (tt,J=11.6, 3.3 Hz, 1H), 2.00 (s, 2H), 1.77-1.74 (d, J=13.3 Hz, 1H), 1.68(d, J=13.3 Hz, 1H), 1.61-1.39 (m, 3H), 1.36-1.24 (m, 1H), 1.19-1.09 (m,2H), 1.07 (s, 1H), 1.01 (s, 9H), 0.76-0.69 (m, 1H); MS (ESI+) m/z 527(M+H).

Example 4rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2,5-dichlorophenyl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 2D, substituting 2-(bromomethyl)-1,4-dichlorobenzene (35.9 mg,0.149 mmol) for 2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.40-7.31 (m, 3H), 7.28 (dd, J=6.5, 1.8 Hz,2H), 7.11 (d, J=8.4 Hz, 1H), 7.04 (dd, J=8.5, 2.6 Hz, 1H), 6.52 (d,J=2.5 Hz, 1H), 5.18 (d, J=6.5 Hz, 1H), 4.71 (d, J=3.0 Hz, 1H), 4.51 (d,J=13.8 Hz, 1H), 4.18 (dd, J=6.6, 2.6 Hz, 1H), 4.10 (d, J=13.8 Hz, 1H),3.13 (t, J=2.9 Hz, 1H), 2.37-2.21 (m, 1H), 1.1.77 (d, J=13.2 Hz, 1H),1.68 (d, J=13.2 Hz, 1H), 1.61-1.39 (m, 3H), 1.34-1.24 (m, 1H), 1.13 (s,2H), 1.04 (s, 9H), 0.69 (d, J=12.4 Hz, 1H); MS (ESI−) m/z 531 (M−H)⁻.

Example 5rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]oxy}-5-phenylpyrrolidine-2-carboxylicacid

To Example 2C (67 mg, 0.167 mmol) and2-chloro-6-methyl-4-(trifluoromethyl)pyridine (65.3 mg, 0.334 mmol) indimethylformamide (1.0 mL), cooled in an ice-bath, was added sodiumhydride (13.35 mg, 0.334 mmol) portionwise. The mixture was stirred atambient temperature for 24 hours. Dichloromethane (10 mL) was added andthe mixture was washed with 1M aqueous HCl and brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified via flashchromatography on 12 g silica gel cartridge, eluting with ethyl acetatein heptanes at 5-60% gradient to provide the title compound, 18 mg(20.25% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.17 (s, 3H), 7.13-7.08(m, 2H), 6.85 (s, 1H), 6.35 (s, 1H), 5.80 (t, J=6.6 Hz, 1H), 5.46 (d,J=7.3 Hz, 1H), 4.67 (d, J=5.4 Hz, 1H), 3.17 (t, J=5.7 Hz, 1H), 2.50 (s,3H), 2.29 (tt, J=11.7, 3.2 Hz, 1H), 1.80 (d, J=10.1 Hz, 2H), 1.60-1.44(m, 3H), 1.31 (td, J=12.4, 11.7, 3.5 Hz, 1H), 1.18 (d, J=12.2 Hz, 2H),1.05 (s, 9H), 0.81-0.67 (m, 1H); MS (ESI−) m/z 531 (M−H)⁻.

Example 6rac-(2R,3S,5R)-3-tert-butyl-4-[(4,6-dimethoxypyrimidin-2-yl)oxy]-1-[di(propan-2-yl)carbamoyl]-5-phenylpyrrolidine-2-carboxylicacid Example 6A rac-(2R,3S,4R,5R)-benzyl3-(tert-butyl)-1-(diisopropylcarbamoyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

To Core 3 (3 g, 7.84 mmol) and triethylamine (3.28 mL, 23.53 mmol) indichloromethane (30 mL) was added diisopropylcarbamic chloride (1.540 g,9.41 mmol) in dichloromethane (10 mL) dropwise. The reaction mixture wasstirred at ambient temperature for 2 hours, warmed to 40° C. overnight,and ethyl acetate (30 mL) and saturated aqueous ammonium chloride (20mL) were added. The aqueous layer was extracted with ethyl acetate. Thecombined organic fractions were dried over MgSO₄, filtered, andconcentrated. Purification via chromatography on an 80 g silica gelcartridge, eluting with ethyl acetate in heptanes at 0-40% gradientprovided the title compound, 2.15 g (53.8% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.45-7.30 (m, 7H), 7.26-7.19 (m, 3H), 5.40 (d, J=8.9 Hz,1H), 5.27 (q, J=12.1 Hz, 2H), 5.19 (dd, J=8.9, 5.3 Hz, 1H), 4.66 (d,J=5.7 Hz, 1H), 3.75 (hept, J=6.7 Hz, 2H), 3.34 (t, J=5.5 Hz, 1H), 1.07(d, J=6.7 Hz, 6H), 1.03 (d, J=6.7 Hz, 6H), 0.97 (s, 9H); MS (ESI+) m/z510 (M+H)⁺.

Example 6B rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(diisopropylcarbamoyl)-4-oxo-5-phenylpyrrolidine-2-carboxylate

The title compound was prepared according to the procedure described inExample 2B, substituting Example 6A for Example 2A. During the reaction,transesterification from benzyl to ethyl ester occurred. Purificationvia chromatography on 40 g silica gel cartridge, eluting with ethylacetate in heptanes at 0-40% gradient, provided the title compound, 1.03g (63.0% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.48 (dd, J=7.2, 2.0 Hz,2H), 7.33 (t, J=7.4 Hz, 1H), 7.28 (s, 2H), 5.04 (s, 1H), 4.61 (d, J=4.6Hz, 1H), 4.31-4.13 (m, 2H), 3.70 (p, J=6.7 Hz, 2H), 2.49 (dd, J=4.5, 1.0Hz, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.17 (d, J=6.7 Hz, 6H), 1.11-1.06 (m,15H); MS (ESI+) m/z 417 (M+H)⁺.

Example 6C rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(diisopropylcarbamoyl)-4-hydroxy-5-phenylpyrrolidine-2-carboxylate

Example 6C was prepared according to the procedure described in Example1C, substituting Example 6B for Example 1B, and2-chloro-4,6-dimethoxypyrimidine for2-chloro-6-methyl-4-(trifluoromethyl)pyridine. ¹H NMR (400 MHz, CDCl₃) δppm 7.66-7.56 (m, 2H), 7.38 (t, J=7.6 Hz, 2H), 7.31-7.26 (m, 1H), 5.39(d, J=6.0 Hz, 1H), 4.30 (pd, J=7.3, 2.8 Hz, 4H), 3.68 (p, J=6.7 Hz, 2H),2.26 (t, J=2.0 Hz, 1H), 2.14 (d, J=6.0 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H),1.26 (d, J=6.6 Hz, 6H), 1.13 (d, J=6.7 Hz, 6H), 1.06 (s, 9H); MS (ESI−)m/z 527.3 (M−H)⁻, MS (ESI+) m/z 419.1 (M+H)⁺.

Example 6Drac-(2R,3S,5R)-3-(tert-butyl)-1-(diisopropylcarbamoyl)-4-((4,6-dimethoxypyrimidin-2-yl)oxy)-5-phenylpyrrolidine-2-carboxylicacid

Example 6D was prepared according to the procedure described in Example5, substituting Example 6C for Example 2C, and2-chloro-4,6-dimethoxypyrimidine for2-chloro-6-methyl-4-(trifluoromethyl)pyridine. ¹H NMR (500 MHz, CDCl₃) δppm 7.27-7.17 (m, 5H), 5.70 (s, 1H), 5.58 (t, J=7.5 Hz, 1H), 5.30 (d,J=7.2 Hz, 1H), 4.64 (d, J=6.5 Hz, 1H), 3.90 (s, 6H), 3.60 (hept, J=6.6Hz, 2H), 3.20 (dd, J=7.7, 6.5 Hz, 1H), 1.23 (d, J=6.6 Hz, 6H), 1.17 (d,J=6.6 Hz, 6H), 1.08 (s, 9H); MS (ESI−) m/z 527.3 (M−H)⁻.

Example 7rac-(2R,3S,5R)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

Example 7 was prepared according to the procedure described in Example1D, substituting Example 6C for Example 1C, and2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene for2-(bromomethyl)-1,4-dichlorobenzene. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.67(d, J=2.3 Hz, 1H), 7.61 (dd, J=8.7, 2.3 Hz, 1H), 7.55-7.49 (m, 2H),7.35-7.29 (m, 2H), 7.27-7.23 (m, 1H), 5.41 (d, J=5.9 Hz, 1H), 5.38 (s,1H), 5.23 (d, J=12.9 Hz, 1H), 4.37-4.32 (m, 2H), 3.86 (s, 3H), 3.63 (h,J=6.4 Hz, 2H), 2.30 (t, J=1.8 Hz, 1H), 1.22 (d, J=6.7 Hz, 6H), 1.10-0.98(m, 15H); MS (ESI+) m/z 579.2 (M+H)⁺.

Example 8(2R*,3S*,4R*,5R*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

Example 8 was obtained via SFC purification of Example 7 using a chiralColumn (WHELK-O S.S, Column Size: 21×250 mm, 5 micron, Ser. No.09/210,901, Concentration: 30 mg/mL in methanol, Co-Solvent: isopropylalcohol) to provide title compound as the second eluent. Thestereochemistry was arbitrarily assigned. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.69 (s, 2H), 7.47-7.42 (m, 2H), 7.25-7.13 (m, 4H), 5.18 (d, J=3.3Hz, 2H), 4.88 (d, J=6.3 Hz, 1H), 4.43 (d, J=5.2 Hz, 1H), 4.34 (d, J=4.5Hz, 1H), 4.18 (q, J=5.2 Hz, 1H), 3.87 (s, 3H), 3.58 (p, J=6.6 Hz, 2H),2.21 (t, J=4.4 Hz, 1H), 0.99 (d, J=6.5 Hz, 6H), 0.97-0.85 (m, 15H); MS(ESI+) m/z 579.2 (M+H).

Example 9(2S*,3R*,4S*,5S*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

The title compound was isolated via SFC chiral separation described inExample 8 as the first eluent. The stereochemistry was arbitrarilyassigned. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.69 (s, 2H), 7.47-7.42 (m,2H), 7.25-7.13 (m, 4H), 5.18 (d, J=3.3 Hz, 2H), 4.88 (d, J=6.2 Hz, 1H),4.43 (d, J=5.3 Hz, 1H), 4.34 (d, J=4.5 Hz, 1H), 4.18 (q, J=5.2 Hz, 1H),3.87 (s, 3H), 3.58 (p, J=6.6 Hz, 2H), 2.21 (t, J=4.4 Hz, 1H), 0.99 (d,J=6.6 Hz, 6H), 0.94 (d, J=6.7 Hz, 6H), 0.91 (s, 9H); MS (ESI+) m/z 579.1(M+H).

Example 10rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-5-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid Example 10A 5-(bromomethyl)-4,6-dimethoxypyrimidine

(4,6-Dimethoxypyrimidin-5-yl)methanol (600 mg, 3.53 mmol) was dissolvedin 35 mL of dichloromethane. The solution was cooled to <5° C. in an icebath and PBr₃ (0.133 mL, 1.410 mmol) was added dropwise. The reactionwas stirred for 10 minutes at ambient temperature, at which point TLCindicated complete consumption of the starting material. Saturatedaqueous sodium bicarbonate (5 mL) was added, and the mixture was stirredfor 5 minutes and extracted with ethyl acetate (3×20 mL). The combinedorganic extracts were washed with brine (20 mL), dried over sodiumsulfate, filtered, and concentrated. The crude material was purified viaflash chromatography, eluting with 0:100 to 10:90 ethyl acetate:heptanesover 20 minutes on a 12 g silica gel column to provide 190 mg of thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.38 (s, 1H), 4.47 (s,2H), 4.04 (s, 6H).

Example 10B rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-((4,6-dimethoxypyrimidin-5-yl)methoxy)-5-phenylpyrrolidine-2-carboxylate

Example 2C (44 mg, 0.110 mmol) and Example 10A (38.3 mg, 0.164 mmol)were dissolved in 1 mL of dry dimethylformamide and the reaction wascooled to <5° C. in an ice bath. Potassium 2-methylpropan-2-olate (1M intetrahydrofuran, 0.12 mL, 0.12 mmol) solution was added dropwise. Afterthe addition was complete, full conversion of Example 10A was observedby LC/MS. The reaction mixture was diluted with methyl tert-butyl ether(10 mL) and quenched with saturated aqueous ammonium chloride (5 mL).The layers were separated and the organic layer was washed with water(10 mL), concentrated in vacuo, and loaded onto a 12 g silica gelcolumn. The column was eluted with 0:100 to 35:65 ethyl acetate:heptanesover 20 minutes to provide 56 mg of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.29 (s, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.20 (dq, J=13.9,7.2 Hz, 3H), 5.11 (d, J=6.4 Hz, 1H), 4.40 (d, J=4.0 Hz, 1H), 4.13 (dd,J=6.4, 3.8 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H), 4.02 (d, J=10.0 Hz, 1H),3.97 (d, J=10.0 Hz, 1H), 3.80 (s, 6H), 2.34 (br s, 1H), 2.18 (br s, 1H),1.68-1.37 (m, 4H), 1.31-1.02 (m, 6H), 1.15 (t, J=7.1 Hz, 3H), 0.94 (s,9H); MS (ESI+) m/z 554.2 (M+H)⁺.

Example 10Crac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-5-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid

Example 10B (56 mg, 0.101 mmol) was dissolved in 0.25 mL oftetrahydrofuran and 0.25 mL of methanol. Lithium hydroxide (1M aqueous,0.506 mL, 0.506 mmol) was added, and the resulting solution was heatedto 40° C. for 16 hours. The vial was cooled to ambient temperature,acidified with 6M aqueous HCl to pH=3, and extracted withdichloromethane (3×10 mL). The combined organic extracts wereconcentrated, loaded onto a 4 g silica gel column, and eluted with 5:95to 100:0 ethyl acetate:heptanes over 10 minutes to provide 34 mg of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.30 (s, 1H), 7.56 (d,J=7.2 Hz, 2H), 7.21 (qd, J=7.6, 6.7, 3.5 Hz, 3H), 5.10 (d, J=6.6 Hz,1H), 4.38 (d, J=4.0 Hz, 1H), 4.20-4.10 (m, 1H), 4.00 (d, J=2.9 Hz, 2H),3.81 (s, 6H), 2.39 (br s, 1H), 2.21 (br s, 1H), 1.62 (d, J=12.7 Hz, 2H),1.47 (s, 2H), 1.26-0.98 (m, 6H), 0.94 (s, 9H); MS (ESI+) m/z 526.1(M+H)⁺.

Example 11rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-2-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid Example 11A 2-(bromomethyl)-4,6-dimethoxypyrimidine

4,6-Dimethoxy-2-methylpyrimidine (5 g, 32.4 mmol) was dissolved incarbon tetrachloride (54.1 mL) and N-bromosuccinimide (5.77 g, 32.4mmol) and azobisisobutyronitrile (0.266 g, 1.622 mmol) were addedsequentially to the pressure tube, which was sealed and heated to 80° C.for 4 hours and 100° C. for 16 hours. The reaction vessel was cooled toambient temperature, concentrated in vacuo, and the resulting crudematerial was purified via flash chromatography, eluting with 0:100 to25:75 ethyl acetate:heptanes on a 120 g silica gel column over 20minutes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm5.92 (s, 1H), 4.39 (s, 2H), 3.95 (s, 6H); MS (ESI+) m/z 235.0 (M+H)⁺.

Example 11B rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-((4,6-dimethoxypyrimidin-2-yl)methoxy)-5-phenylpyrrolidine-2-carboxylate

Example 11A (44 mg, 0.110 mmol) and Example 2C (76.6 mg, 0.328 mmol)were dissolved in 1 mL of dry dimethylformamide and the resultingsolution was cooled to <5° C. in an ice-water bath. Potassiumtert-butoxide (1M in tetrahydrofuran, 0.22 mL, 0.22 mmol) was addeddropwise over 1 minute. After 10 minutes at the same temperature, LC/MSindicated complete conversion. The reaction mixture was diluted withmethyl tert-butyl ether and quenched with saturated aqueous ammoniumchloride. The organic layer was washed with water, concentrated invacuo, loaded onto a 12 g silica gel column, and eluted with 0:100 to35:65 ethyl acetate:heptanes over 20 minutes to provide 53 mg of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.63 (d, J=7.2Hz, 2H), 7.32-7.10 (m, 3H), 5.94 (s, 1H), 5.17 (d, J=6.3 Hz, 1H), 4.47(d, J=3.8 Hz, 1H), 4.35 (dd, J=6.3, 3.3 Hz, 1H), 4.11 (q, J=7.1 Hz, 2H),4.05-3.92 (m, 2H), 3.82 (s, 6H), 2.54 (s, 1H), 2.18 (s, 1H), 1.61-1.55(m, 2H), 1.53-1.47 (m, 2H), 1.30-1.0 (m, 6H), 1.19 (t, J=7.1 Hz, 3H),0.97 (s, 9H); MS (ESI+) m/z 554.2 (M+H)⁺.

Example 11Crac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-2-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid

Example 11B (53 mg, 0.096 mmol) was dissolved in a mixture oftetrahydrofuran (0.25 mL) and methanol (0.250 mL). Aqueous Lithiumhydroxide (1M, 0.479 mL, 0.479 mmol) solution was added. After heatingto 40° C. for 3 hours, additional lithium hydroxide monohydrate (20.08mg, 0.479 mmol) was added, and heating was continued overnight, at whichpoint complete conversion was noted by LC/MS. The reaction flask wascooled to room temperature and acidified with 6M aqueous HCl to pH=3.The mixture was extracted with dichloromethane, the organics wereconcentrated in vacuo, and the crude material was loaded onto a 4 gsilica gel column eluting with 5:95 to 100:0 ethyl acetate:heptanes over10 minutes to provide 31 mg of the title compound. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 7.64 (d, J=7.4 Hz, 2H), 7.20 (dt, J=25.1, 7.3Hz, 3H), 5.95 (s, 1H), 5.16 (d, J=6.4 Hz, 1H), 4.44 (d, J=3.5 Hz, 1H),4.35 (dd, J=6.4, 3.0 Hz, 1H), 3.97 (s, 2H), 3.83 (s, 6H), 2.60 (s, 1H),2.22 (br s, 1H), 1.64 (d, J=9.5 Hz, 2H), 1.48 (s, 2H), 1.31-1.04 (m,6H), 0.97 (s, 9H); MS (ESI+) m/z 526.1 (M+H)⁺.

Example 12rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid Example 12A 2-(dimethylamino)-5-(trifluoromethyl)nicotinaldehyde

3-Bromo-2-chloro-5-(trifluoromethyl)pyridine (5 g, 19.20 mmol) anddimethylformamide (1.932 mL, 24.96 mmol) were dissolved in 100 mL oftoluene, and the reaction mixture was cooled to <−70° C. beforen-butyllithium (9.94 mL, 24.96 mmol) was added dropwise. The reactionmixture was stirred at the same temperature for 30 minutes, quenched bythe addition of 10 mL of 1M aqueous HCl, and warmed to ambienttemperature. The resulting biphasic mixture was stirred for 15 minutes,the layers were separated, and the organic layer was concentrated invacuo. The crude material was purified via flash chromatography, elutingwith 0:100 to 20:80 ethyl acetate:heptanes over 20 minutes on an 80 gsilica gel column to provide 1.91 g of the title compound. ¹H NMR (501MHz, CDCl₃) δ ppm 9.93 (s, 1H), 8.57-8.38 (m, 1H), 8.12 (dd, J=2.0, 1.2Hz, 1H), 3.20 (s, 6H); MS (ESI+) m/z 219.1 (M+H)⁺.

Example 12B (2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)methanol

Example 12A (1.8 g, 8.25 mmol) was dissolved in 17 mL of methanol andthe mixture was cooled in an ice bath to <5° C. before sodiumborohydride (0.312 g, 8.25 mmol) was added in one portion. Afterstirring for 15 minutes at the same temperature, the reaction wascomplete. The volatiles were removed in vacuo and the crude residue waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic extracts were dried over sodium sulfate,filtered, and concentrated to provide the title compound (1.55 g). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.39 (dd, J=2.5, 1.1 Hz, 1H), 7.84 (d, J=2.3Hz, 1H), 4.72 (d, J=5.1 Hz, 2H), 2.99 (s, 6H), 2.54 (t, J=5.5 Hz, 1H);MS (ESI+) m/z 221.0 (M+H)⁺.

Example 12C3-(bromomethyl)-N,N-dimethyl-5-(trifluoromethyl)pyridin-2-amine

Example 12B (1.32, 6.0 mmol) and triphenylphosphine (2.36 g, 9.0 mmol)were dissolved in tetrahydrofuran (30 mL) and the mixture was cooled to<5° C. in an ice bath before adding N-bromosuccinimide (1.6 g, 9.0 mmol)in one portion. After 15 minutes, complete conversion was observed asindicated by LC/MS. The reaction mixture was concentrated toapproximately 5 mL, loaded onto a 40 g silica gel column, and elutedwith 0:100 to 30:70 methyl tert-butyl ether:heptanes over 20 minutes toprovide 240 mg of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm8.39-8.34 (m, 1H), 7.76 (d, J=2.3 Hz, 1H), 4.54 (s, 2H), 3.11 (s, 6H).

Example 12D rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-((2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenylpyrrolidine-2-carboxylate

Example 2C (60 mg, 0.149 mmol) was dissolved in 1 mL ofdimethylformamide. Example 12C (42.3 mg, 0.149 mmol) was added, and thesolution was cooled to <0° C. in an acetone-ice bath. Potassiumtert-butoxide (1M in tetrahydrofuran, 0.149 mL, 0.149 mmol) was addeddropwise. After stirring for 15 minutes at the same temperature, thereaction mixture was diluted with saturated aqueous ammonium chlorideand extracted with methyl tert-butyl ether. The combined methyltert-butyl ether extracts were concentrated in vacuo, which was loadedonto a 12 g silica gel column and was eluted with 0:100 to 35:65 ethylacetate:heptanes over 20 minutes to provide 67 mg of the title compoundas an inseparable mixture of compounds that was carried to thesubsequent step without additional purification. MS (ESI+) m/z 604.1(M+H)⁺.

Example 12Erac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

Lithium hydroxide (24.99 mg, 1.044 mmol) was dissolved in 0.5 mL ofwater and the solution was added to a mixture of Example 12D (63 mg,0.104 mmol) in 0.250 mL of methanol and 0.250 mL of tetrahydrofuran. Thereaction mixture was heated to 40° C. for 16 hours. After cooling toambient temperature, the reaction was neutralized with 6M aqueous HCl topH=3 and extracted with dichloromethane. The combined organic extractswere concentrated in vacuo and purified via flash chromatography,eluting with 10:90 to 100:0 ethyl acetate:heptanes on a 4 g silica gelcolumn over 20 minutes to provide 16 mg of the title compound. ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.22 (t, J=1.5 Hz, 1H), 7.65 (d, J=7.3Hz, 2H), 7.37-6.95 (m, 4H), 5.20 (d, J=6.2 Hz, 1H), 4.52 (d, J=2.7 Hz,1H), 4.36-4.18 (m, 2H), 3.95 (d, J=12.6 Hz, 1H), 2.81 (s, 6H), 2.50 (brs, 1H), 2.21 (br s, 1H), 1.64 (d, J=10.2 Hz, 2H), 1.48 (s, 2H),1.32-1.01 (m, 6H), 0.99 (s, 9H); MS (DCI⁺) m/z 576.2 (M+H)⁺.

Example 13rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylicacid Example 13A rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)-4-nitropyrrolidine-2-carboxylate

A mixture of Core 2 (12.26 g, 35.03 mmol) and triethylamine (11.2 mL,80.57 mmol) in dichloromethane (120 mL) at 0° C. was treated withcyclohexanecarbonyl chloride (6.1 mL, 45.54 mmol). The mixture wasstirred at 0° C. for 30 minutes and at 25° C. for 1 hour. The mixturewas diluted with dichloromethane (150 mL), washed with saturated aqueoussodium bicarbonate (80 mL) and with brine (100 mL), dried over magnesiumsulfate, filtered and concentrated. The residue was purified by silicagel column chromatography (eluted with ½ ethyl acetate/petroleum ether)to provide the title compound (16.0 g, 34.78 mmol, 100% yield). LC/MS(ESI) m/z 461 (M+H)⁺.

Example 13B rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)-4-oxopyrrolidine-2-carboxylate

To a solution of potassium dichromate (53.73 g, 182.63 mmol) in 6 Maqueous hydrochloric acid (480 mL) was added zinc powder (87.01 g,1330.59 mmol) under nitrogen atmosphere. Upon the complete dissolutionof zinc, the freshly prepared chromium(II) chloride solution wastransferred via syringe to a refluxing solution of Example 13A (12 g,26.09 mmol) in ethanol (480 mL) under nitrogen. The mixture was stirredat reflux for 1 hour and was cooled to room temperature. The mixture wasconcentrated. The residue was extracted with dichloromethane (200 mL).The organic layer was washed with aqueous sodium bicarbonate solution(100 mL) and brine (150 mL), dried over magnesium sulfate, filtered andconcentrated to provide a residue which was purified by silica gelcolumn chromatography (eluted with 1/3 ethyl acetate/petroleum ether) toprovide the title compound (4.32 g, 10.07 mmol, 29.4% yield). LC/MS(ESI) m/z 430 (M+H)⁺.

Example 13C rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-hydroxy-5-(2-methoxyphenyl)pyrrolidine-2-carboxylate

To a solution of rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)-4-oxopyrrolidine-2-carboxylate(Example 13B, 4.32 g, 10.07 mmol) in ethanol (30 mL) was added sodiumborohydride (0.761 g, 20.14 mmol) at 0° C. The mixture was stirred at 0°C. for 1 hour and was diluted with water (20 mL). The mixture wasconcentrated. The residue was extracted with dichloromethane (20 mL×3).The combined organic layers were washed with brine (100 mL), dried overmagnesium sulfate, filtered and concentrated to provide a residue whichwas purified by silica gel column chromatography (eluted with ½ ethylacetate/petroleum ether) to provide the title compound (3.23 g, 7.49mmol, 29.4% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.00-8.02 (m, 1H),7.31 (t, J=8.0 Hz, 1H), 7.05 (t, J=12.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H),5.49 (d, J=6.0 Hz, 1H), 4.61 (d, J=4.0 Hz, 1H), 4.80 (d, J=6.0 Hz, 1H),4.23-4.26 (m, 2H), 3.91 (s, 3H), 2.26 (s, 1H), 1.84 (d, J=5.6 Hz, 1H),1.26-1.70 (m, 4H), 1.26-1.35 (m, 6H), 1.04-1.06 (m, 12H), 0.56-0.65 (m,1H); LC/MS (ESI) m/z 432 (M+H)⁺.

Example 13Drac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylicacid

To rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-hydroxy-5-(2-methoxyphenyl)pyrrolidine-2-carboxylate(Example 13C, 60 mg, 0.139 mmol) and2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene (56.1 mg, 0.209mmol) in dimethylformamide (1 mL) cooled in an ice bath was addedpotassium 2-methylpropan-2-olate (23.40 mg, 0.209 mmol) drop wisekeeping the temperature below 0° C. After the addition, the temperaturewas slowly raised to ambient temperature. Methanol (2 mL) and 6M aqueousLiOH (0.5 mL) were added. The mixture was stirred at 45° C. overnight,adjusted pH to 1˜2 by adding 4M HCl in dioxane, and concentrated.Purification via chromatography, eluting with ethyl acetate:methanol(9:1) in heptanes provided the title compound 25 mg (30.4% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.91 (s, 1H), 7.43 (dd, J=8.7, 2.4 Hz, 1H),7.17-7.11 (m, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.93 (s, 1H), 6.92-6.79 (m,2H), 5.50 (d, J=6.2 Hz, 1H), 4.49 (d, J=3.1 Hz, 1H), 4.32 (d, J=13.2 Hz,1H), 4.22 (dd, J=6.4, 2.4 Hz, 1H), 3.99 (d, J=13.2 Hz, 1H), 3.78 (s,3H), 3.76 (s, 3H), 2.51 (s, 1H), 2.23-2.10 (m, 1H), 1.65 (d, J=10.0 Hz,2H), 1.48 (s, 2H), 1.23-1.00 (m, 6H), 0.98 (s, 9H); MS (ESI+) m/z 592.1(M+H)⁺.

Example 14rac-(2R,3S,5R)-3-tert-butyl-4-[(4-chloro-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 13D, substituting 1-(bromomethyl)-4-chloro-2-methoxybenzene for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.88 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.91 (d, J=8.2 Hz,1H), 6.85 (q, J=3.0 Hz, 2H), 6.70 (dd, J=8.1, 2.0 Hz, 1H), 6.59 (d,J=8.1 Hz, 1H), 5.46 (d, J=6.0 Hz, 1H), 4.49 (d, J=3.0 Hz, 1H), 4.25-4.14(m, 2H), 3.92 (d, J=12.9 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 1.65 (d,J=10.1 Hz, 2H), 1.49 (s, 2H), 1.06 (s, 3H), 0.96 (s, 9H); MS (ESI+) m/z558.1 (M+H)⁺.

Example 15rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-[2-(dimethylamino)pyridin-3-yl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylicacid Example 15A rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-(dimethylamino)pyridin-3-yl)-4-nitropyrrolidine-2-carboxylate

A solution of Core 4 (2.0 g, 5.49 mmol) and triethylamine (1.151 mL,8.23 mmol) in dichloromethane (20 mL) at 0° C. was treated withcyclohexanecarbonyl chloride (0.954 mL, 7.13 mmol). The reaction mixturewas stirred at 0° C. for 30 minutes, and was allowed to warm to ambienttemperature. Dichloromethane (20 mL) was added. The mixture was washedwith saturated aqueous NaHCO₃ and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on a 25 g silica gelcartridge eluting with 0-50% ethyl acetate in heptanes to provide thetitle compound 1.58 g, (60.7% yield). ¹H NMR (501 MHz, CDCl₃) δ ppm8.39-7.87 (m, 2H), 7.07 (dd, J=7.8, 4.8 Hz, 1H), 5.87 (t, J=8.0 Hz, 1H),5.53-5.47 (m, 1H), 4.98 (d, J=2.5 Hz, 1H), 4.45-4.33 (m, 2H), 3.09-3.02(m, 1H), 2.88 (d, J=31.3 Hz, 6H), 2.41 (t, J=11.8 Hz, 1H), 1.88-1.69 (m,3H), 1.62 (s, 5H), 1.41 (dt, J=21.4, 7.2 Hz, 3H), 1.34-1.22 (m, 3H),1.12 (d, J=12.4 Hz, 9H); MS (ESI+) m/z 475.2 (M+H).

Example 15B rac-(2R,3S,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-(dimethylamino)pyridin-3-yl)-4-oxopyrrolidine-2-carboxylate

To potassium dichromate (3.37 g, 11.46 mmol) in 6 M aqueous HCl (60 mL)in an ice-bath, zinc (3.86 g, 35 mmol) was added slowly keeping theinternal temperature below 15° C. Complete dissolution of the zincprovided a clear light blue solution. The formed chromium(II) chloridewas transferred to a refluxing solution of Example 15A (0.8 g, 1.686mmol) in ethanol (60 mL). After the addition, LC/MS confirmed theconversion to the intermediate of oxime. The reaction mixture wasrefluxed overnight, cooled to ambient temperature and concentrated tohalf of its volume. The mixture was extracted with ethyl acetate (50mL×3). The organic phase was washed with saturated aqueous NaHCO₃solution and brine, dried over MgSO₄, filtered, and concentrated toprovide a residue which was purified via chromatography on a 24 g silicagel cartridge, eluting with ethyl acetate in heptanes at 0-40% gradientto provide the title compound (120 mg, 16.05% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.27 (dd, J=4.7, 1.9 Hz, 1H), 8.17 (dd, J=7.7, 1.9 Hz,1H), 7.09 (dd, J=7.7, 4.7 Hz, 1H), 5.56 (s, 1H), 4.55 (d, J=4.6 Hz, 1H),4.16 (dddd, J=17.9, 10.6, 7.1, 3.6 Hz, 2H), 2.85 (s, 6H), 2.80 (d, J=4.6Hz, 1H), 1.87-1.77 (m, 1H), 1.69-1.40 (m, 4H), 1.28 (t, J=12.6 Hz, 2H),1.04 (d, J=6.8 Hz, 9H), 1.00-0.80 (m, 4H), 0.52-0.28 (m, 2H); MS (ESI+)m/z 444.2 (M+H)⁺.

Example 15C rac-(2R,3S,4R,5R)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-(dimethylamino)pyridin-3-yl)-4-hydroxypyrrolidine-2-carboxylate

To a solution of Example 15B (120 mg, 0.271 mmol) in ethanol (5 mL)cooled in an ice-bath was added sodium borohydride (20.47 mg, 0.541mmol) slowly. The reaction mixture was stirred for 30 minutes, and wasallowed to warm to ambient temperature. The mixture was concentrated andthe residue was dissolved in dichloromethane and water. The water layerwas extracted with dichloromethane. The combined organics were washedwith brine, dried over MgSO₄, filtered, and concentrated to provide thetitle compound (120 mg, 100% yield) which was used in next step. LC/MS(APCI+) m/z 446.47 (M+H)⁺.

Example 15Drac-(2R,3S,5R)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-(dimethylamino)pyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)pyrrolidine-2-carboxylicacid

To a mixture of Example 15C (60 mg, 0.135 mmol) and2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene (54.3 mg, 0.202mmol) in dimethylformamide (1 mL) cooled in an ice-bath was addedpotassium 2-methylpropan-2-olate (30.2 mg, 0.269 mmol, 0.27 mL, 1.0 M intetrahydrofuran) drop wise. The mixture was stirred at 0-5° C. for 20minutes. LC/MS showed the reaction was complete, and methanol (1.5 mL)and 6M aqueous LiOH (0.5 mL) were added. The mixture was stirred at 50°C. overnight, adjusted to pH 1˜2 by adding 2M aqueous HCl, andconcentrated. The residue was dispersed in dichloromethane (2 mL) andfiltered. Purification by reverse-phase HPLC (Phenomenex® Luna® C8(2) 5μm 100 Å AXIA™ column (30 mm×75 mm) A gradient of acetonitrile (A) and0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-1.0 min 5% A, 1.0-8.5 minute linear gradient 5-100% A,8.5-11.5 minute 100% A, 11.5-12.0 minute linear gradient 95-5% A))provided the title compound (18 mg, 22.07% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.63-8.47 (m, 1H), 8.25-8.14 (m, 1H), 7.52 (d, J=8.3 Hz,1H), 7.19-6.93 (m, 3H), 5.35 (d, J=5.7 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H),4.42-4.31 (m, 1H), 4.16 (d, J=13.8 Hz, 1H), 3.91-3.82 (m, 1H), 3.73 (d,J=10.3 Hz, 3H), 2.87 (s, 3H), 2.73 (s, 3H), 2.62 (d, J=17.2 Hz, 1H),1.84-1.08 (m, 9H), 1.00 (d, J=7.4 Hz, 9H), 0.48 (dd, J=61.9, 12.8 Hz,2H); MS (ESI+) m/z 606.3 (M+H)⁺.

Example 16rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(methanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide

A mixture of Example 2D (50 mg, 0.089 mmol) anddi(1H-imidazol-1-yl)methanone (31.8 mg, 0.196 mmol) in dichloromethane(2 mL) was stirred at 40° C. for 2 hours, and methanesulfonamide (33.9mg, 0.356 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine(0.053 mL, 0.356 mmol) were added. The mixture was stirred at 40° C.overnight, and dichloromethane and water were added. The organic layerwas washed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified with reverse-phase HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/minute (0-1.0 minute 5% A, 1.0-8.5 minute linear gradient5-100% A, 8.5-11.5 minute 100% A, 11.5-12.0 min linear gradient 95-5% A)to provide the title compound (30 mg, 52.8% yield). ¹H NMR (501 MHz,DMSO-d₆) δ ppm 11.95 (s, 2H), 7.82-7.76 (m, 2H), 7.53 (dd, J=8.7, 2.4Hz, 1H), 7.31-7.25 (m, 2H), 7.23-7.18 (m, 1H), 7.07 (d, J=8.6 Hz, 1H),6.90 (d, J=2.4 Hz, 1H), 5.46 (d, J=7.9 Hz, 1H), 4.50 (d, J=12.5 Hz, 1H),4.39-4.29 (m, 2H), 4.17 (d, J=9.1 Hz, 1H), 3.79 (s, 3H), 3.14 (s, 3H),2.44 (t, J=9.3 Hz, 1H), 2.19 (tt, J=11.6, 3.2 Hz, 1H), 1.68 (dd, J=28.2,12.7 Hz, 2H), 1.45 (d, J=12.7 Hz, 1H), 1.34-1.22 (m, 2H), 1.15-0.94 (m,3H), 0.92 (s, 9H), 0.67 (d, J=12.7 Hz, 1H), 0.56 (m, 1H), ); MS (ESI+)m/z 639.1 (M+H)⁺.

Example 17rac-(2R,3S,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 17A rac-(2R,3S,4R,5R)-2-ethyl 1-isopropyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-1,2-dicarboxylate

Core 1 (0.800 g, 2.497 mmol) in dichloromethane (5 mL) was treated withtriethylamine (0.7 mL, 5.02 mmol) followed by isopropyl chloroformate(1M in toluene) (4.2 mL, 4.20 mmol). The reaction mixture was stirred atroom temperature overnight. The mixture was then diluted with 50 mLdichloromethane and washed twice with 1N aqueous HCl (20 mL each) andonce with brine (20 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The resulting crude residue waspurified by silica gel chromatography, eluting with 0 to 40% ethylacetate-heptanes to provide the title compound (0.344 g, 34% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.49 (m, 2H), 7.20 (m, 3H), 5.59 (m, 1H),5.42 (m, 1H), 4.65 (m, 1H), 4.47 (m, 1H), 4.23 (m, 2H), 2.98 (m, 1H),1.27 (m, 3H), 1.05 (d, J=6.3 Hz, 3H), 1.00 (s, 9H), 0.91 (d, J=5.9 Hz,3H); MS (ESI⁺) m/z 407.0 (M+H)⁺.

Example 17B rac-(2R,3S,5R)-2-ethyl 1-isopropyl3-(tert-butyl)-4-oxo-5-phenylpyrrolidine-1,2-dicarboxylate

Potassium dichromate (0.846 g, 2.88 mmol) was dissolved in 6N aqueousHCl (14 mL), and the solution was chilled in an ice bath. Zinc dust(1.522 g, 23.27 mmol) was added under nitrogen in portions over a fewminutes. After the last addition of zinc, the flask was removed from theice bath and allowed to stir at room temperature for 45 minutes undernitrogen until the zinc had fully dissolved. The initially green-bluemixture became clear and brilliant blue. Meanwhile, a solution ofExample 17A (0.344 g, 0.846 mmol) in ethanol (14 mL) was heated to 75°C. The chromium solution was transferred via syringe to a droppingfunnel and added dropwise over 5 minutes to the reaction mixture, whichturned emerald green. The reaction mixture was refluxed for 20 hours.The mixture was cooled to room temperature, and the ethanol wasevaporated in vacuo. Water (25 mL) was added, and the resulting mixturewas extracted three times with dichloromethane (25 mL each). Thecombined organics were dried over Na₂SO₄, filtered and concentrated invacuo. Chromatography on silica gel, eluting with 0 to 30% ethylacetate-heptanes, provided the title compound, 0.066 g (21% yield). ¹HNMR (500 MHz, DMSO-d₆) δ ppm 7.51 (m, 2H), 7.34-7.25 (m, 3H), 4.99 (s,1H), 4.65 (m, 1H), 4.55 (d, J=4.5 Hz, 1H), 4.25-4.14 (m, 2H), 2.62 (m,1H), 1.37-1.00 (m, 18H); MS (ESI⁺) m/z 376.0 (M+H)⁺.

Example 17C rac-(2R,3S,5R)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate

Example 17B (0.079 g, 0.210 mmol) in ethanol (2.5 mL) was cooled in anice bath and then treated in one portion with sodium borohydride (0.021g, 0.568 mmol). The mixture stirred in the ice bath for 10 minutes andat room temperature overnight. The reaction mixture was quenched with 2mL water and concentrated in vacuo. Excess water was removedazeotropically with acetonitrile, and the residue was purified by silicagel chromatography, eluting with 0 to 30% ethyl acetate-heptanes. Thecrude title compound was obtained as a residue (34 mg) and the materialwas used directly into the next step without additional purification. MS(APCI⁺) m/z 378.2 (M+H)⁺.

Example 17D rac-(2R,3S,5R)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-chloro-2-methoxybenzyl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 17C (0.019 g, 0.050 mmol) and2-(bromomethyl)-4-chloro-1-methoxybenzene (Enamine; 0.024 g, 0.101 mmol)in dimethylformamide (0.5 mL) were cooled to 0° C., and the mixture wastreated dropwise with potassium tert-butoxide solution (1M intetrahydrofuran) (0.101 mL, 0.101 mmol). The reaction mixture wasstirred in an ice bath for 1 hour. The mixture was diluted with ethylacetate (5 mL) and washed three times with water (1 mL each time). Thecombined extracts were then dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was used in the next stepwithout further purification. MS (APCI⁺) m/z 532.6 (M+H)⁺.

Example 17Erac-(2R,3S,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 17D (0.027 g, 0.05 mmol) in tetrahydrofuran (1.600 mL) andmethanol (0.4 mL) was treated with lithium hydroxide (1M aqueous, 0.400mL, 0.400 mmol), and the reaction mixture was stirred overnight at 35°C. The reaction mixture was then concentrated in vacuo, and excessmoisture was removed azeotropically with acetonitrile. The material thusobtained was purified by reverse-phase HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A,8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to providethe title compound, 0.0025 g, 9% yield. ¹H NMR (500 MHz, CDCl₃) δ ppm7.40-7.27 (m, 5H), 7.09 (dd, J=8.7, 2.6 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H),6.56 (d, J=2.7 Hz, 1H), 5.02 (d, J=6.1 Hz, 1H), 4.85 (m, 1H), 4.49 (d,J=3.1 Hz, 1H), 4.36 (d, J=13.3 Hz, 1H), 4.09 (dd, J=6.1, 2.7 Hz, 1H),4.04 (d, J=13.2 Hz, 1H), 3.71 (s, 3H), 2.95 (m, 1H), 1.18 (d, J=6.2 Hz,3H), 1.09-1.03 (m, 12H); MS (ESI⁺) m/z 504.0 (M+H)⁺.

Example 18(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

Example 2 (6.55 g) was separated by chiral preparative SFCchromatography using a CHIRALPAK OZ-H, column size 30×250 mm, 5 micron,serial Number: OZH0SANG001-101201, using a concentration of 65 mg/mL inmethanol with 2-propanol cosolvent (30%) at a flow rate of 56 g/min CO₂to provide 2.10 g of the title compound. R_(T) (chiral SFC)=7.9 min; ¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.66 (d, J=7.4 Hz, 2H), 7.44 (dd,J=8.8, 2.4 Hz, 1H), 7.19 (dt, J=26.6, 7.3 Hz, 3H), 7.07-6.89 (m, 2H),5.21 (d, J=6.4 Hz, 1H), 4.49 (d, J=3.4 Hz, 1H), 4.32 (d, J=13.2 Hz, 1H),4.25 (dd, J=6.5, 2.7 Hz, 1H), 3.98 (d, J=13.2 Hz, 1H), 3.77 (s, 3H),2.51 (s, 1H), 2.24 (s, 1H), 1.65 (d, J=9.8 Hz, 2H), 1.48 (s, 2H),1.36-1.03 (m, 5H), 0.99 (s, 9H), 0.79 (d, J=38.3 Hz, 1H); MS (ESI+) m/z562.3 (M+H)⁺.

Example 19(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

Example 2 (6.55 g) was separated by chiral preparative SFCchromatography using a CHIRALPAK OZ-H, column size 30×250 mm, 5 micron,serial Number: OZH0SANG001-101201, using a concentration of 65 mg/mL inmethanol with 2-propanol cosolvent (30%) at a flow rate of 56 g/min CO₂and UV monitoring at 220 nm to provide 1.92 g of(2S,3R,4S,5S)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-5-phenylpyrrolidine-2-carboxylicacid. The absolute structure of the title compound was determined byX-ray crystallography. R_(T) (chiral SFC)=6.0 min; ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 7.66 (d, J=7.4 Hz, 2H), 7.44 (dd, J=8.8, 2.4 Hz,1H), 7.19 (dt, J=26.6, 7.3 Hz, 3H), 7.07-6.89 (m, 2H), 5.21 (d, J=6.4Hz, 1H), 4.49 (d, J=3.4 Hz, 1H), 4.32 (d, J=13.2 Hz, 1H), 4.25 (dd,J=6.5, 2.7 Hz, 1H), 3.98 (d, J=13.2 Hz, 1H), 3.77 (s, 3H), 2.51 (s, 1H),2.24 (s, 1H), 1.65 (d, J=9.8 Hz, 2H), 1.48 (s, 2H), 1.36-1.03 (m, 5H),0.99 (s, 9H), 0.79 (d, J=38.3 Hz, 1H); MS (ESI+) m/z 562.3 (M+H)⁺;[α]^(24.8)=+83.9° (c=0.85, methanol)⁺.

Example 20rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 2D, substituting3-(chloromethyl)-2-methoxy-5-(trifluoromethyl)pyridine for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.2 (s, 2H), 7.65 (d, J=7.3 Hz, 2H), 7.20 (dd, J=8.6, 5.4Hz, 3H), 7.13 (t, J=7.2 Hz, 1H), 5.22 (d, J=6.3 Hz, 1H), 4.51 (d, J=3.1Hz, 1H), 4.38-4.26 (m, 2H), 3.94 (d, J=13.8 Hz, 1H), 3.88 (d, J=0.9 Hz,3H), 2.50 (s, 1H), 2.23 (s, 1H), 1.71-1.58 (m, 2H), 1.48 (s, 2H),1.21-1.12 (m, 2H), 1.00 (d, J=1.0 Hz, 9H), 0.85 (t, J=6.4 Hz, 2H); MS(ESI+) m/z 563.1 (M+H)⁺.

Example 21(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(2-methoxyethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide

A 4 mL vial was charged with a stir bar, a solution of Example 19 (20.0mg, 0.036 mmol) in dichloroethane, and a solution of carbonyldiimidazole(12.8 mg, 2.22 eq, 0.08 mmol) in dichloroethane. The vial was capped andstirred at 42° C. for 2 hours. To the mixture of2-methoxyethanesulfonamide (16.3 mg, 3 eq, 0.107 mmol) indichloromethane was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 16.1μL, 3 eq, 0.107 mmol) and the vial was capped. The vial was stirred at60° C. for another 2 hours. Upon completion, the compound wasconcentrated to dryness and redissolved in 1400 μL of DMSO/methanol (1:1v/v). The material was purified using reverse phase HPLC method TFA8 toobtain title compound (15.4 mg, 63.4%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.61 (d, J=7.5 Hz, 2H), 7.51-7.43 (m, 1H), 7.24 (dt, J=14.2, 6.8 Hz,3H), 7.04 (d, J=8.7 Hz, 1H), 7.00-6.98 (m, 1H), 5.34 (d, J=7.2 Hz, 1H),4.48-4.39 (m, 1H), 4.38 (d, J=5.9 Hz, 1H), 4.30 (t, J=6.6 Hz, 1H), 4.19(d, J=12.6 Hz, 1H), 3.79 (s, 3H), 3.73 (t, J=6.3 Hz, 2H), 3.57-3.52 (m,2H), 3.22 (s, 3H), 2.64 (t, J=6.1 Hz, 1H), 2.33-2.27 (m, 1H), 1.75-1.64(m, 2H), 1.55-1.40 (m, 2H), 1.36-1.25 (m, 1H), 1.19-1.04 (m, 3H), 0.98(s, 9H); MS (APCI+) m/z 683.4 (M+H)⁺.

Example 22(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-N-(1-methylcyclopropane-1-sulfonyl)-5-phenylpyrrolidine-2-carboxamide

The title compound was prepared according to the procedure described inExample 21 substituting 1-methylcyclopropane-1-sulfonamide for2-methoxyethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.56 (d,J=7.3 Hz, 2H), 7.50-7.44 (m, 1H), 7.24 (dt, J=12.8, 6.9 Hz, 3H), 7.04(d, J=8.9 Hz, 1H), 7.00 (s, 1H), 5.36 (d, J=7.4 Hz, 1H), 4.47-4.41 (m,2H), 4.34-4.26 (m, 2H), 4.16 (d, J=12.7 Hz, 1H), 3.79 (s, 3H), 2.70 (t,J=6.0 Hz, 1H), 2.42-2.34 (m, 1H), 1.69 (s, 3H), 1.55-1.45 (m, 3H), 1.42(s, 3H), 1.35 (dd, J=21.3, 9.9 Hz, 0H), 1.13 (dt, J=22.9, 11.5 Hz, 2H),1.01 (s, 2H), 0.98 (s, 9H), 0.81 (s, 2H); MS (APCI+) m/z 679.4 (M+H)⁺.

Example 23(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(cyclopropanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide

The title compound was prepared according to the procedure described inExample 21 substituting cyclopropanesulfonamide for2-methoxyethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.60 (d,J=7.0 Hz, 2H), 7.48 (dd, J=8.4, 2.4 Hz, 1H), 7.29-7.18 (m, 3H), 7.04 (d,J=8.7 Hz, 1H), 6.99 (s, 1H), 5.35 (d, J=7.4 Hz, 1H), 4.44 (d, J=12.7 Hz,1H), 4.40 (d, J=5.9 Hz, 1H), 4.30 (t, J=6.6 Hz, 1H), 4.19 (d, J=12.7 Hz,1H), 3.79 (s, 3H), 2.88-2.79 (m, 1H), 2.68-2.65 (m, 1H), 2.39-2.29 (m,1H), 1.74-1.66 (m, 2H), 1.54-1.41 (m, 2H), 1.37-1.26 (m, 2H), 1.23-1.04(m, 5H), 0.98 (s, 9H), 0.97-0.91 (m, 2H); MS (APCI+) m/z 665.4 (M+H)⁺.

Example 24(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(ethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide

The title compound was prepared according to the procedure described inExample 21 substituting ethanesulfonamide for2-methoxyethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.61 (d,J=7.5 Hz, 2H), 7.48 (d, J=8.9 Hz, 1H), 7.23 (dq, J=13.0, 7.2 Hz, 3H),7.04 (d, J=8.6 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 5.34 (d, J=7.3 Hz, 1H),4.47-4.37 (m, 2H), 4.31 (t, J=6.7 Hz, 1H), 4.18 (d, J=12.6 Hz, 1H), 3.79(s, 3H), 3.29 (dq, J=14.3, 7.2 Hz, 1H), 2.64 (t, J=6.0 Hz, 1H),2.33-2.27 (m, 1H), 1.74-1.65 (m, 2H), 1.54-1.41 (m, 2H), 1.37-1.25 (m,1H), 1.21 (t, J=7.4 Hz, 3H), 1.18-1.05 (m, 3H), 0.98 (s, 9H), 0.78-0.70(m, 1H); MS (APCI+) m/z 653.4 (M+H)⁺.

Example 25(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(dimethylsulfamoyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide

The title compound was prepared according to the procedure described inExample 21 substituting N,N-dimethylsulfonamide for2-methoxyethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.58 (d,J=7.5 Hz, 2H), 7.50-7.46 (m, 1H), 7.25 (dt, J=13.1, 7.0 Hz, 3H), 7.04(d, J=8.7 Hz, 1H), 7.02-6.99 (m, 1H), 5.35 (d, J=7.3 Hz, 1H), 4.44 (d,J=12.7 Hz, 1H), 4.41 (d, J=5.8 Hz, 1H), 4.33-4.29 (m, 1H), 4.18 (d,J=12.7 Hz, 1H), 3.79 (s, 3H), 2.79 (s, 5H), 2.69-2.67 (m, 1H), 2.37-2.30(m, 1H), 1.74-1.66 (m, 3H), 1.54-1.41 (m, 1H), 1.32 (s, 1H), 1.13 (dd,J=22.0, 11.4 Hz, 3H), 0.97 (s, 9H), 0.77-0.71 (m, 1H); MS (APCI+) m/z668.4 (M+H)⁺.

Example 26(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(methanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide

The title compound was prepared according to the procedure described inExample 21 substituting methanesulfonamide for2-methoxyethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64-7.59(m, 2H), 7.50-7.46 (m, 1H), 7.24 (dt, J=15.2, 7.1 Hz, 3H), 7.04 (d,J=8.7 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 5.34 (d, J=7.3 Hz, 1H), 4.45 (d,J=12.6 Hz, 1H), 4.37 (d, J=6.4 Hz, 1H), 4.31 (t, J=6.9 Hz, 1H), 4.21 (d,J=12.6 Hz, 1H), 3.79 (s, 3H), 3.12 (s, 3H), 2.63 (t, J=6.4 Hz, 1H), 2.31(m, 1H), 1.74-1.65 (m, 2H), 1.53-1.40 (m, 2H), 1.36-1.25 (m, 1H),1.20-1.03 (m, 4H), 0.98 (s, 9H), 0.79-0.69 (m, 1H); MS (APCI+) m/z 639.3(M+H)⁺.

Example 27(2R,3S,4R,5R)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 substituting Core 1 for Core 5 in Example 31A. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.65 (s, 2H), 7.43 (dd, J=8.6, 2.5 Hz, 1H), 7.19 (t,J=7.4 Hz, 2H), 7.12 (d, J=7.1 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.96 (s,1H), 5.20 (d, J=6.5 Hz, 1H), 4.42 (s, 1H), 4.31 (d, J=13.2 Hz, 1H), 4.22(s, 1H), 3.97 (d, J=13.3 Hz, 1H), 3.76 (s, 3H), 3.33 (s, 1H), 2.68-2.60(m, 1H), 2.56-2.50 (m, 1H), 1.61 (s, 2H), 1.40 (t, J=5.1 Hz, 2H),1.33-1.27 (m, 1H), 1.25 (s, 3H), 0.98 (s, 10H), 0.85 (td, J=6.0, 5.4,3.7 Hz, 2H); MS (ESI+) m/z 593 (M+H)⁺.

Example 28(2R,3S,4R,5R)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]oxy}-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 substituting Core 1 for Core 5 in Example 31A and2-chloro-6-methyl-4-(trifluoromethyl)pyridine for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene in Example 31D. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.52 (d, J=7.6 Hz, 2H), 7.11 (t, J=7.4 Hz,2H), 7.05 (d, J=7.1 Hz, 1H), 6.95 (s, 1H), 6.13 (s, 1H), 5.90 (dd,J=6.5, 3.3 Hz, 1H), 5.35 (d, J=6.4 Hz, 1H), 4.51 (d, J=3.8 Hz, 1H), 3.32(s, 1H), 2.54 (s, 1H), 2.42 (s, 3H), 1.69-1.50 (m, 2H), 1.43-1.34 (m,2H), 1.34-1.19 (m, 3H), 1.05 (s, 9H), 0.99-0.96 (m, 3H), 0.88-0.80 (m,2H); MS (ESI+) m/z 563 (M+H)⁺.

Example 29rac-(2R,3S,4R,5R)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 substituting Core 1 for Core 5 in Example 31A. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.69-7.60 (m, 2H), 7.43 (dd, J=8.6, 2.3 Hz, 1H),7.20 (t, J=7.3 Hz, 2H), 7.14 (d, J=6.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H),6.96 (d, J=2.1 Hz, 1H), 5.14 (d, J=6.5 Hz, 1H), 4.49-4.39 (m, 1H), 4.31(d, J=13.2 Hz, 1H), 4.27-4.21 (m, 1H), 3.96 (d, J=13.2 Hz, 1H), 3.76 (s,3H), 3.50-3.39 (m, 1H), 3.19 (s, 2H), 2.66-2.61 (m, 1H), 2.57-2.49 (m,0H), 1.82-1.69 (m, 1H), 1.66-1.54 (m, 1H), 1.41 (t, J=12.4 Hz, 1H), 1.25(s, 3H), 1.23-1.09 (m, 3H), 0.98 (s, 9H), 0.89-0.78 (m, 1H); MS (ESI+)m/z 592 (M+H)⁺.

Example 30(2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 using the second eluting diastereomer in Example 31C andtreating as described in Example 31D-31E. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.65 (s, 2H), 7.43 (dd, J=8.6, 2.5 Hz, 1H), 7.19 (t, J=7.4 Hz, 2H),7.12 (d, J=7.1 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.96 (s, 1H), 5.20 (d,J=6.5 Hz, 1H), 4.42 (s, 1H), 4.31 (d, J=13.2 Hz, 1H), 4.22 (s, 1H), 3.97(d, J=13.3 Hz, 1H), 3.76 (s, 3H), 3.33 (s, 1H), 2.68-2.60 (m, 1H),2.56-2.50 (m, 1H), 1.61 (s, 2H), 1.40 (t, J=5.1 Hz, 2H), 1.33-1.27 (m,1H), 1.25 (s, 3H), 0.98 (s, 10H), 0.85 (td, J=6.0, 5.4, 3.7 Hz, 2H); MS(ESI+) m/z 592 (M+H)⁺.

Example 31(2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid Example 31A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-4-nitro-5-phenylpyrrolidine-2-carboxylateand (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-((1S,3S)-3-methoxycyclohexanecarbonyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

To a solution of Core 5 (1.037 g, 3.24 mmol) and triethylamine (1.353mL, 9.71 mmol) in dichloromethane (8 mL) at 25° C. was added dropwiserac-(1R,3R)-3-methoxycyclohexanecarbonyl chloride (1.143 g, 6.47 mmol)as a solution in 4 mL of dichloromethane. After 30 minutes, the reactionmixture was quenched with saturated aqueous ammonium chloride (50 mL)and extracted with 200 mL of dichloromethane. The organic extracts wereconcentrated in vacuo and purified using a 80 g silica gel cartridgewith 5-100% ethyl acetate/heptanes over 40 minutes to provide(2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-((1S,3S)-3-methoxycyclohexanecarbonyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate(1.395 g, 3.03 mmol, 94% yield) (mixture of diastereomers). ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.56 (t, J=6.6 Hz, 2H), 7.25 (p, J=7.3 Hz, 3H),5.74-5.53 (m, 2H), 4.66 (dd, J=7.3, 3.7 Hz, 1H), 4.24 (qd, J=7.0, 1.6Hz, 2H), 3.49-3.28 (m, 1H), 3.19 (s, 3H), 2.99 (dt, J=5.9, 3.4 Hz, 1H),2.55 (s, 1H), 1.80 (d, J=13.2 Hz, 1H), 1.69-1.54 (m, 2H), 1.48-1.38 (m,2H), 1.28 (td, J=7.1, 1.6 Hz, 3H), 1.21-1.12 (m, 2H), 1.00 (d, J=2.0 Hz,9H), 0.88-0.79 (m, 1H); MS (ESI+) m/z 461 (M+H)⁺.

Example 31B (2S,3R,5S)-ethyl3-(tert-butyl)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-4-oxo-5-phenylpyrrolidine-2-carboxylateand (2S,3R,5S)-ethyl3-(tert-butyl)-1-((1S,3S)-3-methoxycyclohexanecarbonyl)-4-oxo-5-phenylpyrrolidine-2-carboxylate

Example 31A (1.350 g, 2.93 mmol) was dissolved in ethanol (75 mL), thesolution was degassed with bubbling nitrogen for about 20 minutes, andthe mixture was heated to 75° C. under nitrogen. A separate solution ofCrCl₂ was prepared by dissolving potassium dichromate (2.93 g, 9.97mmol) in aqueous hydrochloric acid, 6M (75 mL) and adding Zn (inportions while cooling in an ice bath, keeping the internal temperaturearound 25° C.), keeping the system under nitrogen. The color of thesolution changed from dark brown to dark green to clear light blue. Themixture was added via cannula over 20 minutes to the solution ofstarting material. The reaction was warmed to 80° C. and was heated for19 hours. The reaction mixture was cooled to room temperature and theethanol was removed in vacuo. The mixture was diluted with water (50 mL)and extracted with dichloromethane (3×200 mL). The combined extractswere dried over sodium sulfate, filtered, concentrated and purifiedusing a 40 g silica gel cartridge and eluting with 0-15% ethylacetate/heptanes over 20 minutes then 10 minutes at 30% ethylacetate/heptanes and 30-100% ethyl acetate/heptanes over 10 minutes toprovide (2S,3R,5S)-ethyl3-(tert-butyl)-1-((1S,3S)-3-methoxycyclohexanecarbonyl)-4-oxo-5-phenylpyrrolidine-2-carboxylate(0.752 g, 1.751 mmol, 59.7% yield) as a mixture of diastereomers. ¹H NMR(90° C., 400 MHz, DMSO-d₆,) 6 ppm 7.56 (s, 2H), 7.30 (dt, J=32.7, 7.4Hz, 3H), 5.10 (s, 1H), 4.72 (d, J=4.3 Hz, 1H), 4.16 (dtd, J=7.4, 6.2,5.5, 1.9 Hz, 2H), 3.46-3.39 (m, 1H), 3.19 (d, J=8.3 Hz, 1H), 3.17 (s,3H), 2.67-2.49 (m, 1H), 1.88-1.73 (m, 1H), 1.72-1.52 (m, 1H), 1.49-1.34(m, 2H), 1.29-1.25 (m, 1H), 1.21 (td, J=7.1, 2.0 Hz, 3H), 1.03 (d, J=3.9Hz, 10H), 1.00 (d, J=2.5 Hz, 1H), 0.93-0.86 (m, 1H); MS (ESI+) m/z 430(M+H)⁺.

Example 31C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

Example 31B (0.750 g, 1.746 mmol) was dissolved in ethanol (8.73 mL) andsodium borohydride (0.132 g, 3.49 mmol) was added in one portion aftercooling the reaction to <5° C. in an ice-water bath. The reactionmixture was stirred at the same temperature for 30 minutes,concentrated, and partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate. The organics were concentrated and purifiedusing a 40 g silica gel cartridge and eluting with 0-100% ethylacetate/heptanes over 30 minutes to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate(0.242 g, 0.561 mmol, 32.1% yield) as the second eluent. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.57 (d, J=7.5 Hz, 2H), 7.26 (t, J=7.5 Hz, 2H), 7.19(t, J=7.3 Hz, 1H), 4.95 (d, J=6.8 Hz, 1H), 4.41-4.32 (m, 2H), 4.14 (q,J=7.1 Hz, 2H), 3.96 (s, 1H), 3.42 (d, J=4.2 Hz, 1H), 3.17 (s, 3H), 2.53(s, 1H), 2.22 (s, 1H), 1.73 (d, J=13.9 Hz, 1H), 1.60 (d, J=13.4 Hz, 1H),1.38 (ddd, J=13.9, 11.4, 2.7 Hz, 1H), 1.26 (d, J=3.4 Hz, 1H), 1.27-1.19(m, 4H), 1.22-1.08 (m, 1H), 1.18-1.10 (m, 1H), 0.98 (s, 9H), 0.88-0.79(m, 1H); MS (ESI+) m/z 432 (M+H)⁺. The other diastereomer was alsoisolated (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((1S,3S)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate(0.245 g, 0.568 mmol, 32.5% yield) as the first eluent. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.58 (d, J=7.3 Hz, 2H), 7.27 (t, J=7.6 Hz, 3H), 7.18 (d,J=7.3 Hz, 1H), 5.00 (d, J=6.8 Hz, 1H), 4.40-4.30 (m, 2H), 4.14 (q, J=7.1Hz, 2H), 3.92 (s, 1H), 3.29 (s, 1H), 2.72 (s, 3H), 2.53 (s, 1H), 2.20(s, 1H), 1.70-1.49 (m, 2H), 1.44-1.32 (m, 3H), 1.32-1.18 (m, 5H), 0.97(s, 9H); MS (ESI+) m/z 432 (M+H)⁺.

Example 31D (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

Example 31C (90 mg, 0.209 mmol) and2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene (84 mg, 0.313 mmol)were dissolved in dry dimethylformamide (0.5 mL). After cooling in anice bath, potassium 2-methylpropan-2-olate (0.30 mL, 0.250 mmol)solution was added dropwise over 2 minutes. The reaction mixture wasstirred in the ice bath for 30 minutes, acidified with 1M aqueous HCl(10 drops), warmed to room temperature, diluted with water (0.5 mL), andextracted with dichloromethane (2×3 mL). The organics were concentratedand loaded onto a 12 g silica gel column and were eluted with 5-100%ethyl acetate/heptanes over 20 minutes to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate(116 mg, 0.187 mmol, 90% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.63(d, J=17.2 Hz, 2H), 7.44 (dd, J=8.8, 2.3 Hz, 1H), 7.21 (t, J=7.4 Hz,2H), 7.15 (d, J=7.1 Hz, 1H), 7.03-6.97 (m, 2H), 5.16 (d, J=6.2 Hz, 1H),4.52 (d, J=3.3 Hz, 1H), 4.29 (d, J=13.1 Hz, 2H), 4.13-4.04 (m, 2H), 3.93(d, J=13.1 Hz, 1H), 3.75 (d, J=0.8 Hz, 3H), 3.43 (s, 1H), 3.18 (d, J=0.9Hz, 3H), 2.60 (s, 1H), 1.74 (d, J=13.8 Hz, 1H), 1.61 (d, J=12.9 Hz, 1H),1.48-1.36 (m, 1H), 1.25-1.18 (m, 2H), 1.15 (td, J=7.1, 0.9 Hz, 3H), 0.99(d, J=1.0 Hz, 9H), 0.89-0.78 (m, 4H); MS (APCI+) m/z 620 (M+H)⁺.

Example 31E(2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

Example 31D (64 mg, 0.103 mmol) was dissolved in methanol (0.5 mL) andtetrahydrofuran (0.500 mL). LiOH (20 mg, 0.835 mmol) in water (0.250 mL)was added. The reaction mixture was warmed at 35° C. for 48 hours. Thesolvent was removed, and the reaction mixture was acidified with 1Maqueous HCl (30 drops). The crude material was loaded onto a 12 g silicagel column and was eluted with an ethyl acetate/ethanol/heptanes solventsystem over 20 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid (50 mg, 0.085 mmol, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.69-7.60 (m, 2H), 7.43 (dd, J=8.6, 2.3 Hz, 1H), 7.20 (t, J=7.3 Hz, 2H),7.14 (d, J=6.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H),5.14 (d, J=6.5 Hz, 1H), 4.49-4.39 (m, 1H), 4.31 (d, J=13.2 Hz, 1H),4.27-4.21 (m, 1H), 3.96 (d, J=13.2 Hz, 1H), 3.76 (s, 3H), 3.50-3.39 (m,1H), 3.19 (s, 2H), 2.66-2.61 (m, 1H), 2.57-2.49 (m, 0H), 1.82-1.69 (m,1H), 1.66-1.54 (m, 1H), 1.41 (t, J=12.4 Hz, 1H), 1.25 (s, 3H), 1.23-1.09(m, 3H), 0.98 (s, 9H), 0.89-0.78 (m, 1H); MS (ESI+) m/z 592 (M+H)⁺.

Example 32(2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 using the first eluting diastereomer from Example 31C andsubstituting 1-(bromomethyl)-2-methoxy-4-(trifluoromethyl)benzene for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene in Example 31D. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.71-7.51 (m, 2H), 7.21 (t, J=7.3 Hz, 2H),7.15 (d, J=7.1 Hz, 1H), 7.05 (s, 1H), 6.99 (d, J=7.9 Hz, 1H), 6.81 (d,J=7.9 Hz, 1H), 5.18 (d, J=6.4 Hz, 1H), 4.44 (s, 1H), 4.28 (d, J=13.6 Hz,1H), 4.20 (d, J=6.3 Hz, 1H), 3.96 (d, J=13.6 Hz, 1H), 3.75 (s, 3H), 3.33(s, 1H), 2.70-2.59 (m, 2H), 2.51 (s, 1H), 1.61 (s, 2H), 1.48-1.34 (m,2H), 1.27 (d, J=10.7 Hz, 4H), 0.98 (s, 9H), 0.89-0.78 (m, 2H); MS (ESI+)m/z 592 (M+H)⁺.

Example 33(2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 substituting1-(bromomethyl)-2-methoxy-4-(trifluoromethyl)benzene for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene in Example 31D. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.65 (d, J=7.4 Hz, 2H), 7.26-7.09 (m, 3H),7.05 (d, J=1.6 Hz, 1H), 6.99 (dd, J=7.9, 1.6 Hz, 1H), 6.83 (d, J=7.9 Hz,1H), 5.13 (d, J=6.3 Hz, 1H), 4.46 (d, J=3.2 Hz, 1H), 4.28 (d, J=13.6 Hz,1H), 4.23 (d, J=6.2 Hz, 1H), 3.96 (d, J=13.6 Hz, 1H), 3.74 (s, 3H), 3.43(s, 1H), 3.19 (s, 3H), 2.71-2.58 (m, 1H), 2.52 (s, 1H), 1.77 (d, J=12.3Hz, 1H), 1.61 (d, J=12.5 Hz, 1H), 1.42 (ddd, J=13.9, 11.2, 2.7 Hz, 1H),1.31-1.13 (m, 4H), 0.99 (s, 9H), 0.89-0.79 (m, 1H); MS (ESI+) m/z 592(M+H)⁺.

Example 34rac-(2R,3S,4R,5R)-3-tert-butyl-1-[(cyclobutyloxy)carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid Example 34A Cyclobutylchloroformate

Cyclobutanol (1.02 g, 14.15 mmol) was dissolved in dichloromethane (10mL) and pyridine (1.2 mL, 14.84 mmol) was added to the reaction mixture.The reaction mixture was cooled to 0° C. with an ice bath. Triphosgene(2.06 g, 6.94 mmol) was added in portions to the well stirred reactionmixture. The reaction mixture was stirred at 0° C. for 1 hour and wasallowed to warm to ambient temperature and stir for an additional 3hours. The reaction mixture was poured into 1 M aqueous HCl (50 mL) andextracted with dichloromethane (3×50 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated to provide the titlecompound (1.3 g, 68%), which was used without additional purification.¹H NMR (400 MHz, CDCl₃) 4.85-4.93 (m, 1H), 2.31-2.38 (m, 2H), 2.06-2.16(m, 2H), 1.57-1.64 (m, 2H).

Example 34B rac-1-cyclobutyl 2-ethyl(2R,3S,4R,5R)-3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-1,2-dicarboxylate

rac-(2R,3S,4R,5R)-Ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate (Core 1, 1.01g, 3.15 mmol) was dissolved in dichloromethane (10 mL) andtrimethylamine (0.9 mL, 6.46 mmol) was added, followed by cyclobutylchloroformate (Example 34A, 1.3 g, 9.66 mmol). The reaction mixture wasstirred at ambient temperature for 4 hours, at which point it wascomplete. The reaction mixture was diluted with dichloromethane (50 mL)and washed with 1M aqueous HCl (2×50 mL) and brine. The organic layerwas dried over sodium sulfate, filtered and concentrated to provide ˜2 gof crude product. The residue was purified by silica gel chromatography(dichloromethane, R_(f)=0.25) to provide the title compound (1.31 g,99%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.56-7.45 (m, 2H),7.30-7.15 (m, 3H), 5.66-5.54 (m, 1H), 5.45 (d, J=8.8 Hz, 1H), 4.79-4.70(m, 1H), 4.50 (d, J=3.8 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.99 (t, J=3.7Hz, 1H), 2.40-1.36 (m, 6H), 1.28 (t, J=7.1 Hz, 3H), 1.01 (s, 9H); MS(ESI+) m/z 419 (M+H)⁺.

Example 34C rac-1-cyclobutyl 2-ethyl(2R,3S,5R)-3-(tert-butyl)-4-oxo-5-phenylpyrrolidine-1,2-dicarboxylate

rac-(2R,3S,4R,5R)-1-Cyclobutyl 2-ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-1,2-dicarboxylate (Example 34B, 700 mg, 1.673 mmol) was dissolved in 30 mL of ethanol and thesolution was heated to 75° C. A separate solution of CrCl₂ was preparedby dissolving pyridinium dichromate (1673 mg, 5.69 mmol) in 30 mL of 6Maqueous HCl and adding Zn (3.00 g, 27.5 mmol, in portions while coolingin an ice bath). The suspension was stirred until all Zn dissolved,leaving a brilliant blue solution. The CrCl₂ solution was transferredvia cannula over 15 minutes to the solution of starting material andheating was continued for 16 hours. The temperature was maintainedbetween 70 and 75° C. during the addition. Immediately after theaddition was complete, very clean conversion to the oxime intermediatewas observed. Heating was continued between 75 and 80° C. overnight(total 16 hours). The reaction was cooled to room temperature, dilutedwith water and extracted with dichloromethane (3×30 mL). The combinedorganic extracts were washed with brine and dried over sodium sulfate.After filtration and concentration, the crude residue was dissolvedethanol (10 mL). A separate solution of HCl/ethanol was prepared by theaddition of 1 mL of acetyl chloride to 5 mL of ethanol at 0° C. Themixture was poured into the reaction flask and the mixture was heated to45° C. for 1 hour. The reaction mixture was concentrated in vacuo andloaded onto a 12 g silica gel column. The column was eluted with 0-30%ethyl acetate/heptanes over 20 minutes to provide the title compound(373 mg, 58%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.50-7.45 (m,2H), 7.33-7.28 (m, 2H), 7.27-7.21 (m, 1H), 4.94 (s, 1H), 4.87-4.75 (m,1H), 4.62 (d, J=4.5 Hz, 1H), 4.19 (qd, J=7.0, 1.5 Hz, 2H), 2.57 (dd,J=4.5, 1.1 Hz, 1H), 2.28-2.07 (m, 2H), 1.91-1.45 (m, 4H), 1.23 (t, J=7.1Hz, 3H), 1.05 (s, 9H); MS (ESI+) m/z 388 (M+H)⁺.

Example 34D rac-1-cyclobutyl 2-ethyl(2R,3S,4R,5R)-3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate

Example 34C (310 mg, 0.80 mmol) was dissolved in methanol (4 mL), andthe reaction mixture was cooled to 0° C. Sodium borohydride (62.9 mg,1.66 mmol) was added and the reaction mixture was stirred at 0° C. for 1hour. The mixture was warmed to ambient temperature for another 1 hour.The solvent was removed in vacuo, the residue was extracted withdichloromethane (50 mL), and the organics were washed with saturatedaqueous NaHCO₃ (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered,and concentrated to provide crude product, which was purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound (117.5 mg, 38%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 7.54-7.48 (m, 2H), 7.27-7.19 (m, 2H), 7.19-7.12 (m, 1H),4.83 (d, J=6.7 Hz, 1H), 4.71 (p, J=7.0 Hz, 1H), 4.31 (dd, J=6.7, 4.4 Hz,1H), 4.23 (d, J=4.8 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 2.24 (t, J=4.7 Hz,1H), 2.20-2.03 (m, 2H), 1.81-1.41 (m, 4H), 1.24 (t, J=7.0 Hz, 3H), 0.98(s, 9H); MS (ESI+) m/z 390 (M+H)⁺.

Example 34E rac-1-cyclobutyl 2-ethyl(2R,3S,4R,5R)-3-(tert-butyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 34D (33.6 mg, 0.086 mmol) and2-methoxy-4-(trifluoromethyl)benzyl bromide (36.9 mg, 0.137 mmol) weredissolved in dimethylformamide (1 mL). The reaction mixture was cooledto 0° C., potassium tert-butoxide (1M in tetrahydrofuran, 0.14 mL, 0.14mmol) was added dropwise and the reaction was stirred at ambienttemperature for 1 hour. The reaction was diluted with methanol (1 mL)and purified by reverse-phase preparative HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (36.6 mg, 73%). ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 7.59-7.52 (m, 2H), 7.24-7.12 (m, 3H), 7.06 (d,J=1.5 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 5.01 (d,J=6.2 Hz, 1H), 4.73 (p, J=7.0 Hz, 1H), 4.34 (d, J=3.4 Hz, 1H), 4.26 (d,J=13.3 Hz, 1H), 4.20 (dd, J=6.2, 2.8 Hz, 1H), 4.15-4.07 (m, 2H), 3.95(d, J=13.3 Hz, 1H), 3.74 (s, 3H), 2.44 (t, J=3.2 Hz, 1H), 2.21-2.04 (m,2H), 1.82-1.40 (m, 4H), 1.17 (t, J=7.1 Hz, 3H), 0.99 (s, 9H); MS (ESI+)m/z 578 (M+H)⁺.

Example 34Frac-(2R,3S,4R,5R)-3-tert-butyl-1-[(cyclobutyloxy)carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

Example 34E (33.6 mg, 0.058 mmol) was dissolved in methanol (1 mL) andtetrahydrofuran (1 mL). LiOH (1 M, 0.5 mL, 0.5 mmol) was added and thereaction mixture was heated to 50° C. for 16 hours. The reaction mixturewas purified by reverse-phase preparative HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (18.6 mg, 58%). ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 7.62-7.55 (m, 2H), 7.23-7.11 (m, 3H), 7.05 (d,J=1.6 Hz, 1H), 7.00 (dd, J=7.5, 1.5 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H),4.99 (d, J=6.2 Hz, 1H), 4.77-4.68 (m, 1H), 4.31 (d, J=3.2 Hz, 1H), 4.26(d, J=13.5 Hz, 1H), 4.18 (dd, J=6.2, 2.5 Hz, 1H), 3.96-3.90 (m, 1H),3.74 (s, 3H), 2.48-2.47 (m, 1H), 2.21-2.03 (m, 2H), 1.83-1.38 (m, 4H),0.99 (s, 9H); MS (ESI+) m/z 550 (M+H)⁺.

Example 35rac-(2R,3S,4R,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-1-[(cyclobutyloxy)carbonyl]-5-phenylpyrrolidine-2-carboxylicacid Example 35A rac-1-cyclobutyl 2-ethyl(2R,3S,4R,5R)-3-(tert-butyl)-4-((5-chloro-2-methoxybenzyl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 34D (47.0 mg, 0.121 mmol) and2-(bromomethyl)-4-chloro-1-methoxybenzene (41.1 mg, 0.175 mmol) weredissolved in N,N-dimethylformamide (1 mL). The reaction was cooled to 0°C., and potassium tert-butoxide (1M in tetrahydrofuran, 0.18 mL, 0.18mmol) was added dropwise and the reaction was stirred at ambienttemperature for 1 hours. The reaction mixture was diluted with methanol(1 mL) and purified by reverse-phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes lineargradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes lineargradient 95-10% A) to provide the title compound (47.4 mg, 72%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.60-7.54 (m, 2H), 7.25-7.19 (m, 2H),7.19-7.13 (m, 1H), 7.10 (dd, J=8.7, 2.8 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H),6.64 (d, J=2.7 Hz, 1H), 5.01 (d, J=6.2 Hz, 1H), 4.73 (p, J=7.0 Hz, 1H),4.34 (d, J=3.3 Hz, 1H), 4.23-4.09 (m, 4H), 3.88 (d, J=13.0 Hz, 1H), 3.66(s, 3H), 2.44 (t, J=3.0 Hz, 1H), 2.21-2.04 (m, 2H), 1.82-1.40 (m, 4H),1.19 (t, J=7.1 Hz, 3H), 0.99 (s, 9H); MS (ESI+) m/z 544 (M+H)⁺.

Example 35Brac-(2R,3S,4R,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-1-[(cyclobutyloxy)carbonyl]-5-phenylpyrrolidine-2-carboxylicacid

Example 35B (44.4 mg, 0.082 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction mixturewas purified by reverse-phase preparative HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (22.2 mg, 53%). ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 7.60-7.54 (m, 2H), 7.25-7.18 (m, 2H), 7.18-7.12(m, 1H), 7.10 (dd, J=8.7, 2.7 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 6.62 (d,J=2.7 Hz, 1H), 4.99 (d, J=6.3 Hz, 1H), 4.73 (p, J=7.0 Hz, 1H), 4.30 (d,J=3.2 Hz, 1H), 4.24-4.18 (m, 1H), 4.17 (dd, J=6.3, 2.5 Hz, 1H), 3.88 (d,J=13.1 Hz, 1H), 3.66 (s, 3H), 2.36 (s, 1H), 2.21-2.02 (m, 2H), 1.84-1.39(m, 4H), 0.99 (s, 9H); MS (ESI+) m/z 516 (M+H)⁺.

Example 36(2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 38F substituting Example 38D for Example 34E. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.65-7.56 (m, 2H), 7.27-7.11 (m, 4H), 6.78 (d, J=8.7 Hz,1H), 6.75 (d, J=2.5 Hz, 1H), 4.97 (d, J=6.4 Hz, 1H), 4.64 (p, J=6.2 Hz,1H), 4.29 (d, J=3.3 Hz, 1H), 4.22 (d, J=13.1 Hz, 1H), 4.16 (dd, J=6.3,2.5 Hz, 1H), 3.89 (d, J=13.1 Hz, 1H), 3.80 (s, 1H), 3.67 (s, 3H), 1.06(d, J=6.3 Hz, 3H), 0.99 (s, 9H), 0.89 (d, J=6.2 Hz, 3H); MS (APCI+) m/z548 (M+H)⁺.

Example 37(2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 substituting 4-bromo-2-(bromomethyl)-1-methoxybenzene for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene in Example 31D. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.65 (d, J=7.4 Hz, 2H), 7.28-7.10 (m, 4H),6.78 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 5.13 (d, J=6.5 Hz, 1H),4.44 (d, J=3.2 Hz, 1H), 4.27-4.17 (m, 2H), 3.92 (d, J=13.2 Hz, 1H), 3.67(s, 3H), 3.44 (s, 1H), 3.20 (s, 3H), 2.72-2.59 (m, 2H), 2.53 (s, 1H),1.77 (d, J=13.6 Hz, 1H), 1.62 (d, J=12.8 Hz, 1H), 1.42 (ddd, J=13.9,11.2, 2.7 Hz, 1H), 1.32-1.17 (m, 2H), 0.99 (s, 9H), 0.90-0.78 (m, 2H);MS (APCI+) m/z 602 (M+H)⁺.

Example 38(2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 38A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-1,2-dicarboxylate

To a solution of Core 5 (2.193, 6.84 mmol) in dichloromethane (20 mL)and triethylamine (4 mL, 28.7 mmol) was added a 1M solution of isopropylchloroformate (15 mL, 15.00 mmol) in toluene dropwise via additionfunnel over about 3 minutes. After 30 minutes, additional 1M isopropylchloroformate (6 mL) was added and after another 30 minutes additional1M isopropyl chloroformate (6 mL) was added. The reaction mixture wasstirred at room temperature for 3 hours more. The reaction mixture wasdiluted with dichloromethane (200 mL) and a small amount of ethanol andwashed with saturated aqueous sodium bicarbonate (50 mL), dried oversodium sulfate, filtered, and concentrated. The crude material waspurified using a 40 g silica gel cartridge with a gradient of 5-100%ethyl acetate/heptanes over 30 minutes to provide (2S,3R,4S,5S)-2-ethyl1-isopropyl 3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-1,2-dicarboxylate(2.790 g, 6.88 mmol, 100% yield). ¹H NMR (400 MHz, 120° C., DMSO-d₆) δppm 7.56-7.46 (m, 2H), 7.30-7.15 (m, 3H), 5.61 (dd, J=8.8, 3.3 Hz, 1H),5.43 (d, J=8.8 Hz, 1H), 5.33 (dd, J=6.6, 3.2 Hz, 0H), 4.67 (pd, J=6.1,0.7 Hz, 1H), 4.50 (d, J=3.8 Hz, 1H), 4.25 (qd, J=7.1, 0.6 Hz, 2H), 2.98(t, J=3.6 Hz, 1H), 1.29 (td, J=7.0, 0.7 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H),1.03-0.98 (m, 9H), 0.92 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 407 (M+H)⁺.

Example 38B (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-oxo-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38A (2.366 g, 5.82 mmol) was dissolved in ethanol (75 mL) andthe solution was heated to 71° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (5.82 g, 19.79 mmol) inhydrochloric acid (6M, 75 mL) and adding Zn (10.47 g, 160 mmol) inportions while cooling in an ice bath. The suspension was stirred untilall almost all of the Zn dissolved, leaving a brilliant blue solution.The CrCl₂ solution was transferred via cannula over 15 minutes to thesolution of starting material (cooled to 65° C. during the addition) andheating was continued at 80° C. for 16 hours. The mixture was cooled toroom temperature, reduced in volume in vacuo, diluted with water, andextracted with 3×200 mL of dichloromethane. The combined extracts werewashed with brine, dried over sodium sulfate, filtered, and concentratedin vacuo. The crude material was loaded onto a 80 g silica gel columnand eluted with 0-100% ethyl acetate/heptanes over 40 minutes to provide(2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-oxo-5-phenylpyrrolidine-1,2-dicarboxylate (0.793 g,2.112 mmol, 36.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.48-7.40 (m,2H), 7.33-7.27 (m, 2H), 7.26-7.19 (m, 1H), 4.91 (s, 1H), 4.77-4.69 (m,1H), 4.62 (d, J=4.4 Hz, 1H), 4.19 (qd, J=7.1, 1.4 Hz, 2H), 2.56 (dd,J=4.5, 0.9 Hz, 1H), 1.22 (t, J=7.1 Hz, 3H), 1.11 (d, J=6.2 Hz, 3H), 1.05(s, 9H), 0.98 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 376 (M+H)⁺.

Example 38C (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38B (0.611 g, 1.627 mmol) was dissolved in ethanol (8.14 mL) andsodium borohydride (0.123 g, 3.25 mmol) was added in one portion aftercooling the reaction to <5° C. in an ice-water bath. The reaction wasstirred at the same temperature for 30 minutes, concentrated, andpartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organics were concentrated and purified using a 40 gsilica gel cartridge and eluting with 0-100% ethyl acetate/heptanes over40 minutes on to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate (0.506 g,1.340 mmol, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.50 (dd, J=8.1,1.5 Hz, 2H), 7.19-7.27 (m, 2H), 7.09-7.19 (m, 1H), 4.82 (d, J=6.7 Hz,1H), 4.62 (pd, J=6.2, 1.1 Hz, 1H), 4.27-4.35 (m, 1H), 4.22 (dd, J=4.8,1.2 Hz, 1H), 4.10-4.19 (m, 2H), 3.84 (d, J=7.4 Hz, 1H), 2.21-2.28 (m,1H), 1.24 (td, J=7.1, 1.0 Hz, 3H), 1.04 (dd, J=6.3, 1.2 Hz, 3H), 0.98(d, J=1.1 Hz, 9H), 0.90 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 378 (M+H)⁺.

Example 38D (2S,3R,4S,5S)-2-ethyl 1-isopropyl4-((5-bromo-2-methoxybenzyl)oxy)-3-(tert-butyl)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38C (36 mg, 0.095 mmol) and4-bromo-2-(bromomethyl)-1-methoxybenzene (53.4 mg, 0.191 mmol) weredissolved in dry dimethylformamide (0.5 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (0.200 mL, 0.200 mmol) solutionwas added dropwise over 2 minutes. After 30 minutes, the reaction wasacidified with 1M aqueous HCl (10 drops) and warmed to room temperature.The mixture was concentrated and loaded onto a 12 g silica gel columnand eluted with 5-100% ethyl acetate/heptanes over 20 minutes to provide(2S,3R,4S,5S)-2-ethyl 1-isopropyl4-((5-bromo-2-methoxybenzyl)oxy)-3-(tert-butyl)-5-phenylpyrrolidine-1,2-dicarboxylate(57 mg, 0.099 mmol, 104% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.56(dd, J=7.1, 1.6 Hz, 2H), 7.26-7.13 (m, 4H), 6.81-6.74 (m, 2H), 4.99 (d,J=6.0 Hz, 1H), 4.65 (dt, J=12.4, 6.2 Hz, 1H), 4.35 (d, J=3.2 Hz, 1H),4.24-4.17 (m, 2H), 4.14 (qd, J=7.1, 2.6 Hz, 2H), 3.88 (dd, J=12.9, 0.9Hz, 1H), 3.68-3.63 (m, 3H), 2.44 (t, J=2.9 Hz, 1H), 1.20 (t, J=7.1 Hz,3H), 1.06 (d, J=6.2 Hz, 3H), 1.00 (s, 9H), 0.92 (d, J=7.5 Hz, 3H); MS(APCI+) m/z 577 (M+H)⁺.

Example 38E (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((4-methoxy-[1,1′-biphenyl]-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38D (125 mg, 0.217 mmol), phenylboronic acid (31.7 mg, 0.260mmol), cesium carbonate (212 mg, 0.650 mmol) anddichlorobis(triphenylphosphine)palladium(II) (10 mg, 0.014 mmol) werecombined in a 4 mL vial and put under nitrogen. To this mixture wasadded degassed dioxane (1084 μL). The reaction mixture was heated in analuminum block at 95° C. for 2 hours, concentrated, loaded onto a 12 gsilica gel column, and eluted with 5-100% ethyl acetate/heptanes over 20minutes to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((4-methoxy-[1,1′-biphenyl]-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate(91 mg, 0.159 mmol, 73.2% yield). MS (APCI+) m/z 574 (M+H)⁺.

Example 38F(2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 38E (91 mg, 0.159 mmol) was dissolved in methanol (0.5 mL). LiOH(25 mg, 1.044 mmol) in water (0.500 mL) was added and a precipitateformed. Tetrahydrofuran (0.500 mL) was added and everything dissolved.The reaction mixture was warmed at 45° C. for 16 hours. The solvent wasremoved, and the reaction was acidified with 1M aqueous HCl (30 drops).The crude material was loaded onto a 12 g silica gel column and elutedwith an ethyl acetate/ethanol/heptanes solvent system over 20 minutes toprovide(2S,3R,4S,5S)-3-(tert-butyl)-1-(isopropoxycarbonyl)-4-((4-methoxy-[1,1′-biphenyl]-3-yl)methoxy)-5-phenylpyrrolidine-2-carboxylicacid (48 mg, 0.088 mmol, 55.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.64-7.59 (m, 2H), 7.47-7.36 (m, 5H), 7.32-7.24 (m, 1H), 7.16 (dd,J=8.2, 6.7 Hz, 2H), 7.11-7.07 (m, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.91 (d,J=8.5 Hz, 1H), 5.00 (d, J=6.4 Hz, 1H), 4.64 (p, J=6.2 Hz, 1H), 4.35-4.28(m, 2H), 4.22 (dd, J=6.4, 2.7 Hz, 1H), 4.01 (d, J=12.6 Hz, 1H), 3.72 (s,3H), 2.52 (t, J=3.0 Hz, 1H), 1.06 (d, J=6.2 Hz, 3H), 1.00 (s, 9H), 0.89(d, J=6.2 Hz, 3H); MS (APCI+) m/z 546 (M+H)⁺.

Example 39(2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31, substituting 4-bromo-2-(bromomethyl)-1-methoxybenzene for2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene in Example 31D andtreating the resulting product as described in Example 38E-38F. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.67 (d, J=6.7 Hz, 2H), 7.48-7.36 (m, 5H),7.33-7.23 (m, 1H), 7.19 (t, J=7.3 Hz, 2H), 7.15-7.05 (m, 1H), 7.01 (d,J=2.5 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 5.15 (d, J=6.5 Hz, 1H), 4.44 (d,J=3.1 Hz, 1H), 4.33 (d, J=12.6 Hz, 1H), 4.30-4.23 (m, 1H), 4.03 (d,J=12.6 Hz, 1H), 3.73 (s, 3H), 3.44 (s, 1H), 3.19 (s, 3H), 2.69-2.60 (m,2H), 2.61-2.52 (m, 1H), 1.77 (d, J=11.6 Hz, 1H), 1.67-1.57 (m, 2H), 1.42(td, J=13.4, 12.3, 2.7 Hz, 1H), 1.21-1.10 (m, 2H), 0.99 (s, 9H),0.92-0.77 (m, 1H); MS (APCI+) m/z 600 (M+H)⁺.

Example 40(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 40A (2S,3R,4S,5S)-2-ethyl 1-isopropyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38C (140 mg, 0.371 mmol) and5-bromo-3-(bromomethyl)-2-methoxypyridine (157 mg, 0.559 mmol) weredissolved in dry dimethylformamide (0.8 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (0.80 mL, 0.80 mmol) solution wasadded dropwise over 20 minutes. After 20 minutes, the reaction wasacidified with 1M aqueous HCl (10 drops) and warmed to room temperature.The mixture was concentrated and loaded onto a 24 g silica gel columnand eluted with 5-50% ethyl acetate/heptanes over 20 minutes to provide(2S,3R,4S,5S)-2-ethyl 1-isopropyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-5-phenylpyrrolidine-1,2-dicarboxylate(0.170 g, 0.294 mmol, 79% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.00(d, J=2.5 Hz, 1H), 7.58-7.52 (m, 2H), 7.25-7.15 (m, 3H), 7.02 (dd,J=2.4, 1.1 Hz, 1H), 5.00 (d, J=6.2 Hz, 1H), 4.65 (p, J=6.2 Hz, 1H), 4.36(d, J=3.1 Hz, 1H), 4.25-4.18 (m, 2H), 4.13 (qd, J=7.1, 2.8 Hz, 2H), 3.85(d, J=13.5 Hz, 1H), 3.78 (s, 3H), 2.44 (t, J=2.8 Hz, 1H), 1.20-1.16 (m,3H), 1.06 (d, J=6.2 Hz, 3H), 1.01 (s, 9H), 0.90 (d, J=6.2 Hz, 3H); MS(APCI+) m/z 577 (M+H)⁺.

Example 40B(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 40A (38 mg, 0.066 mmol) was dissolved in methanol (0.5 mL). LiOH(12 mg, 0.501 mmol) in water (0.500 mL) was added followed bytetrahydrofuran (0.500 mL). The reaction was warmed at 45° C. for 16hours. The solvent was removed and the reaction was acidified with 1Maqueous HCl (30 drops). The crude material was loaded onto a 12 g silicagel column and purified twice with an ethyl acetate/ethanol/heptanessolvent system over 20 minutes to provide(2S,3R,4S,5S)-4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-1-(isopropoxycarbonyl)-5-phenylpyrrolidine-2-carboxylicacid (20 mg, 0.036 mmol, 55.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.00 (d, J=2.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.24-7.17 (m, 2H), 7.17-7.11(m, 1H), 7.00 (dd, J=2.4, 1.2 Hz, 1H), 4.99 (d, J=6.3 Hz, 1H), 4.64 (p,J=6.3 Hz, 1H), 4.30 (d, J=3.0 Hz, 1H), 4.24-4.17 (m, 2H), 3.86 (dd,J=13.8, 1.1 Hz, 1H), 3.78 (s, 3H), 1.26 (s, 1H), 1.06 (d, J=6.2 Hz, 3H),1.00 (s, 9H), 0.89 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 549 (M+H)⁺.

Example 41(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid Example 41A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate

To a cooled (ice bath) mixture of Core 5 (2.0 g, 6.24 mmol) andtriethylamine (2.61 mL, 18.73 mmol) in dichloromethane (20 mL) was addedcyclohexanecarbonyl chloride (1.002 mL, 7.49 mmol) dropwise. The mixturewas stirred in the ice-bath for 10 minutes and allowed to warm to roomtemperature. Dichloromethane (10 mL) was added. The mixture was washedwith brine, dried over MgSO₄, filtered, and concentrated to provide thetitle compound (2.45 g, 91%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.73-7.61(m, 2H), 7.38 (q, J=8.2, 7.4 Hz, 3H), 5.46 (d, J=9.0 Hz, 1H), 5.37 (dd,J=8.9, 4.5 Hz, 1H), 4.82 (d, J=4.7 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.15(d, J=4.6 Hz, 1H), 2.06 (ddt, J=11.5, 7.0, 3.5 Hz, 1H), 1.68 (dd,J=33.2, 12.5 Hz, 2H), 1.55-1.41 (m, 4H), 1.38 (t, J=7.1 Hz, 3H),1.34-1.13 (m, 3H), 1.07 (s, 9H), 0.59 (d, J=12.6 Hz, 1H); MS (ESI+) m/z431 (M+H)⁺.

Example 41B (2S,3R,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-oxo-5-phenylpyrrolidine-2-carboxylate

To potassium dichromate (4.65 g, 15.79 mmol) in 6 M aqueous HCl (60 mL),zinc (5.3 g, 81 mmol) was added under N₂ atmosphere. Completedissolution of zinc provided a clear light blue solution. The formedchromium(II) chloride was transferred to the refluxing solution ofExample 41A (1 g, 2.323 mmol) in ethanol (60 mL). The reaction mixturewas refluxed overnight. The mixture was cooled and concentrated to halfof its volume and extracted with dichloromethane (30 mL×3). The combinedorganic phase was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was dissolved in ethanol (2 mL) and added to aprepared solution of acetyl chloride (1 mL) in ethanol (4 mL) cooling inan ice-bath. The mixture was heated to 60° C. for 2 hours, concentrated,and dissolved in ethyl acetate (50 mL) and saturated aqueous NaHCO₃ (30mL). The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated to provide a residue which purified viachromatography on a 40 g silica gel cartridge, eluting with ethylacetate in heptanes at 0-30% gradient to provide the title compound (688mg, 74.1% yield).

Example 41C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-hydroxy-5-phenylpyrrolidine-2-carboxylate

To Example 41B (730 mg, 1.827 mmol) in ethanol (10 mL) cooled in anice-bath was added sodium borohydride (138 mg, 3.65 mmol) portionwise.The mixture was stirred in ice-bath for 30 minutes and was allowed towarm to room temperature. LC/MS indicated the reaction was finished andshowed two product peaks at ratio about 3 to 1, with the title compoundas the major isomer. Saturated NH₄Cl (2 mL) was added, and the mixturewas concentrated, dissolved in dichloromethane (30 mL), washed withbrine, dried over MgSO₄, filtered, and concentrated. Purification viachromatography on a 40 g silica gel cartridge eluting with ethylacetate/methanol (9:1) in heptanes at 0-40% gradient provided the titlecompound (480 mg, 65.4% yield). LC/MS (APCI+) m/z 402 (M+H)⁺.

Example 41D(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid

To Example 41C and 3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine(121 mg, 0.448 mmol) in dimethylformamide (2 mL) cooled in an ice-bath,potassium 2-methylpropan-2-olate (62.9 mg, 0.560 mmol, 0.56 mL, 1.0 M intetrahydrofuran) was added dropwise. The mixture was stirred in theice-bath for 20 minutes, and allowed to warm to room temperature.Methanol (1.5 mL) and 6M aqueous LiOH (0.5 mL) was added. The mixturewas stirred at 50° C. overnight, and adjusted to pH 1˜2 by adding 2Maqueous HCl. The solvent was removed and dichloromethane was (1 mL)added. The reaction mixture was filtered through a syringe filter andthe filtrate was purified via chromatography, eluting with methanol indichloromethane at 0-20% gradient to provide title compound, 130 mg(61.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (td, J=1.9, 0.8 Hz,1H), 7.66 (d, J=7.3 Hz, 2H), 7.28-7.08 (m, 4H), 5.23 (d, J=6.3 Hz, 1H),4.51 (d, J=3.1 Hz, 1H), 4.38-4.24 (m, 2H), 3.95 (d, J=13.9 Hz, 1H), 3.89(s, 3H), 2.51 (s, 1H), 2.23 (s, 1H), 1.65 (d, J=9.5 Hz, 2H), 1.49 (s,2H), 1.17 (d, J=73.3 Hz, 6H), 1.01 (s, 9H); MS (ESI+) m/z 563 (M+H)⁺.

Example 42(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared following the procedures used in Example38E-38F using the material from Example 40A. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.20 (d, J=2.6 Hz, 1H), 7.67-7.58 (m, 2H), 7.44 (d, J=4.9 Hz, 4H),7.37-7.30 (m, 1H), 7.28 (dd, J=2.5, 1.1 Hz, 1H), 7.14 (t, J=7.5 Hz, 2H),7.09-7.02 (m, 1H), 5.00 (d, J=6.3 Hz, 1H), 4.68-4.59 (m, 1H), 4.34-4.28(m, 2H), 4.24 (dd, J=6.4, 2.4 Hz, 1H), 3.97 (d, J=13.2 Hz, 1H), 3.85 (d,J=0.7 Hz, 3H), 2.54 (t, J=2.8 Hz, 1H), 1.06 (d, J=6.2 Hz, 3H), 1.01 (s,9H), 0.90-0.85 (m, 3H); MS (APCI+) m/z 547 (M+H)⁺.

Example 43(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclohexyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 43A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-cyclohexyl-2-methoxypyridin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

In a 4 mL vial, Example 40A (22.7 mg, 0.039 mmol, 1.0 eq) anddichloro[4,5-dichloro-1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl, 3.38 mg, 0.0039 mmol, 0.1 eq) were dissolved intetrahydrofuran (500 μL), flushed with nitrogen and stirred at roomtemperature. Cyclohexylzinc bromide (0.5 M, 235 μL, 0.12 mmol, 3.0 eq)was added and the reaction was stirred at room temperature for 30minutes. The solvent was removed under a stream of nitrogen,reconstituted in DMSO, and purified reverse phase HPLC/MS method TFA7.MS (APCI+) m/z 581.1 (M+H)⁺.

Example 43B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclohexyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 43A was dissolved in 3:2 tetrahydrofuran/methanol (500 μL). LiOHmonohydrate (16 mg, 0.39 mmol, 10 eq) in H₂O (100 μL) was added and thereaction mixture was stirred at 45° C. After material started toprecipitate, a few drops methanol were added. After 4 hours the solventwas removed under a stream of nitrogen. The residue was acidified using800 μL 1 M aqueous HCl, and was diluted with 400 μL CH₃CN. The reactionwas loaded directly into an injection loop and was purified using prepLC method TFA8 to provide the title compound (8.8 mg, 40.6% yield). ¹HNMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 7.75 (d, J=2.5 Hz,1H), 7.60-7.52 (m, 2H), 7.25-7.18 (m, 2H), 7.18-7.10 (m, 1H), 6.83 (d,J=2.5 Hz, 1H), 4.97 (d, J=6.3 Hz, 1H), 4.63 (p, J=6.2 Hz, 1H), 4.31 (d,J=3.2 Hz, 1H), 4.27-4.12 (m, 2H), 3.87 (d, J=13.2 Hz, 1H), 3.75 (s, 3H),2.48-2.45 (m, 1H), 2.35-2.27 (m, 1H), 1.73 (d, J=38.3 Hz, 5H), 1.45-1.11(m, 5H), 1.05 (d, J=6.2 Hz, 3H), 0.98 (s, 9H), 0.88 (d, J=6.1 Hz, 3H);MS (APCI+) m/z 553.1 (M+H)⁺.

Example 44(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 44A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-cyclopentyl-2-methoxypyridin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

In a 4 mL vial, Example 40A (22.7 mg, 0.039 mmol, 1.0 eq) anddichloro[4,5-dichloro-1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl, 3.38 mg, 0.0039 mmol, 0.1 eq) were dissolved intetrahydrofuran (500 μL), flushed with nitrogen and stirred at roomtemperature. Cyclopentylzinc bromide (0.5 M, 235 μL, 0.12 mmol, 3.0 eq)was added and reaction was stirred at room temperature for 30 minutes.The solvent was removed under a stream of nitrogen, reconstituted inDMSO, and purified using reverse phase method TFA8. MS (APCI+) m/z 567.1(M+H)⁺.

Example 44B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 44A was dissolved in 3:2 tetrahydrofuran/methanol (500 μL). LiOHmonohydrate (16 mg, 0.39 mmol, 10 eq) in H₂O (100 μL) was added and thereaction mixture was stirred at 45° C. After material started toprecipitate, a few drops methanol were added. After 4 hours, the solventwas removed under a stream of nitrogen. The residue was acidified using800 μL 1 M aqueous HCl, and diluted with 400 μL CH₃CN. The reaction wasloaded directly into an injection loop and purified using prep LC methodTFA8 to provide the title compound (11.0 mg, 52.1% yield). ¹H NMR (400MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 7.77 (d, J=2.4 Hz, 1H),7.60-7.53 (m, 2H), 7.24-7.09 (m, 3H), 6.90 (d, J=2.3 Hz, 1H), 4.97 (d,J=6.3 Hz, 1H), 4.62 (p, J=6.3 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 4.23-4.13(m, 2H), 3.86 (d, J=13.2 Hz, 1H), 3.75 (s, 3H), 2.83-2.78 (m, 1H), 2.46(t, J=2.9 Hz, 1H), 1.94-1.88 (m, 2H), 1.78-1.58 (m, 4H), 1.56-1.30 (m,2H), 1.05 (d, J=6.3 Hz, 3H), 0.98 (s, 9H), 0.88 (d, J=6.2 Hz, 3H); MS(APCI+) m/z 539.1 (M+H)⁺.

Example 45(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 45A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 40A (0.140 g, 0.242 mmol) in tetrahydrofuran (2.4 mL) wastreated with PdCl₂(dppf)([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 8.8 mg,0.012 mmol), followed by dropwise addition of cyclobutylzinc(II) bromide(0.5M in tetrahydrofuran) (0.97 mL, 0.48 mmol) at room temperature. Thereaction was allowed to stir for a total of 2 hours at room temperature.The reaction mixture was quenched with saturated aqueous NH₄Cl solutionand the solvent was reduced under a stream of nitrogen. The crudeproduct was purified using a 25 g silica gel cartridge with a gradientof 5-50% ethyl acetate/heptanes over 20 minutes to provide(2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate(113 mg, 0.204 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.76(d, J=2.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.26-7.11 (m, 3H), 6.93 (d, J=2.4Hz, 1H), 5.00 (d, J=6.2 Hz, 1H), 4.64 (p, J=6.2 Hz, 1H), 4.34 (d, J=3.3Hz, 1H), 4.23-4.17 (m, 2H), 4.10 (qd, J=7.1, 2.8 Hz, 2H), 3.87 (dd,J=13.0, 0.8 Hz, 1H), 3.75 (s, 3H), 3.41-3.27 (m, 1H), 2.50-2.42 (m, 2H),2.24 (ddt, J=9.0, 6.1, 2.5 Hz, 2H), 2.01-1.79 (m, 3H), 1.15 (t, J=7.0Hz, 3H), 1.05 (d, J=6.2 Hz, 3H), 0.99 (s, 9H), 0.89 (d, J=6.1 Hz, 3H);MS (ESI+) m/z 552 (M+H)⁺.

Example 45B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a solution of Example 45A (113 mg, 0.204 mmol) in tetrahydrofuran (1mL) and methanol (1.0 mL) was added lithium hydroxide (34 mg, 1.420mmol) in water (1 mL) and the reaction was heated at 45° C. overnight.The solvent was removed under a stream of nitrogen. The crude materialwas acidified with 2M aqueous HCl (342 uL) and purified using a 24 gsilica gel column. The column was eluted with an ethylacetate/ethanol/heptanes solvent system to provide(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-(isopropoxycarbonyl)-5-phenylpyrrolidine-2-carboxylicacid (80 mg, 0.152 mmol, 74.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.76 (d, J=2.4 Hz, 1H), 7.61-7.57 (m, 2H), 7.24-7.10 (m, 3H), 6.93 (td,J=1.7, 0.9 Hz, 1H), 4.98 (d, J=6.3 Hz, 1H), 4.63 (ddd, J=11.8, 6.6, 5.8Hz, 1H), 4.29 (d, J=3.2 Hz, 1H), 4.24-4.15 (m, 2H), 3.88 (dd, J=13.1,0.9 Hz, 1H), 3.76 (d, J=0.7 Hz, 3H), 3.39-3.26 (m, 1H), 2.71-2.57 (m,1H), 2.32-2.16 (m, 2H), 2.03-1.81 (m, 3H), 1.06 (d, J=6.2 Hz, 3H), 0.99(d, J=0.8 Hz, 9H), 0.89 (d, J=6.2 Hz, 3H), 0.87-0.79 (m, 1H); MS (APCI+)m/z 525 (M+H)⁺.

Example 46(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid Example 46A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

Example 31C (27 mg, 0.063 mmol) and2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (30 mg, 0.117 mmol) weredissolved in dry dimethylformamide (0.5 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (0.100 mL, 0.100 mmol) solutionwas added dropwise over 2 minutes. The mixture was acidified with 1Maqueous HCl (10 drops) and warmed to room temperature. The mixture wasconcentrated and loaded onto a 12 g silica gel column and was elutedwith 5-100% methyl tert-butyl ether/heptanes over 20 minutes to provide(2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate(33 mg, 0.054 mmol, 87% yield). MS (APCI+) m/z 608 (M+H)⁺.

Example 46B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid

Example 46A (33 mg, 0.054 mmol) was dissolved in methanol (0.5 mL).Lithium hydroxide (17 mg, 0.710 mmol) and water (0.500 mL) were addedand a precipitate formed. Tetrahydrofuran (0.500 mL) was added andeverything dissolved. The reaction mixture was warmed at 45° C.overnight. The solvent was removed, and the reaction was acidified with1M aqueous HCl (30 drops). The crude material was loaded onto a 12 gsilica gel column and was eluted with an ethyl acetate/ethanol/heptanessolvent system over 20 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid (24 mg, 0.041 mmol, 76% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.67 (d, J=7.4 Hz, 2H), 7.22 (t, J=7.4 Hz, 2H), 7.16 (d, J=7.1 Hz, 1H),7.12 (dd, J=8.6, 2.6 Hz, 1H), 6.87 (d, J=2.6 Hz, 1H), 6.74 (d, J=8.6 Hz,1H), 5.13 (d, J=6.6 Hz, 1H), 4.38 (d, J=3.7 Hz, 1H), 4.26-4.16 (m, 2H),3.94 (d, J=12.2 Hz, 1H), 3.65 (s, 3H), 3.44 (s, 1H), 3.20 (s, 3H),3.04-3.00 (m, 1H), 2.70-2.58 (m, 1H), 2.52 (s, 1H), 1.76 (d, J=13.7 Hz,1H), 1.62 (d, J=12.7 Hz, 1H), 1.42 (ddd, J=13.8, 11.2, 2.7 Hz, 1H),1.30-1.21 (m, 2H), 1.18 (s, 9H), 0.96 (s, 9H), 0.90-0.81 (m, 2H); MS(APCI+) m/z 580 (M+H)⁺.

Example 47(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 47A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38C and 2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (53 mg,0.206 mmol) were dissolved in dry dimethylformamide (0.5 mL). Aftercooling in an ice bath, potassium 2-methylpropan-2-olate (0.216 mL,0.216 mmol) solution was added dropwise over 2 minutes. After 30minutes, the reaction was acidified with 1M aqueous HCl (10 drops) andwarmed to room temperature. The mixture was concentrated, loaded onto a12 g silica gel column, and eluted with 5-100% methyl tert-butylether/heptanes over 20 minutes to provide (2S,3R,4S,5S)-2-ethyl1-isopropyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylate(73 mg, 0.132 mmol, 98% yield). MS (APCI+) m/z 554 (M+H)⁺.

Example 47B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 47A (78 mg, 0.141 mmol) was dissolved in methanol (0.5 mL). LiOH(23 mg, 0.960 mmol) in water (0.500 mL) was added and a precipitateformed. Tetrahydrofuran was added (0.500 mL) and everything dissolved.The reaction mixture was warmed at 45° C. After warming at 45° C.overnight, LC/MS showed some desired product but mostly startingmaterial. Additional LiOH (20 mg) was added in addition to 0.3 mLtetrahydrofuran. The reaction mixture was warmed at 45° C. for 6 hours.The solvent was removed, and the reaction was acidified with 1M aqueousHCl (30 drops). The crude material was loaded onto a 12 g silica gelcolumn and was eluted with an ethyl acetate/ethanol/heptanes solventsystem over 20 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-(isopropoxycarbonyl)-5-phenylpyrrolidine-2-carboxylicacid (51 mg, 0.097 mmol, 68.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.65-7.59 (m, 2H), 7.19 (td, J=7.1, 1.1 Hz, 2H), 7.15-7.09 (m, 2H), 6.89(d, J=2.5 Hz, 1H), 6.77-6.71 (m, 1H), 4.96 (d, J=6.4 Hz, 1H), 4.62 (ddd,J=11.8, 6.8, 5.8 Hz, 1H), 4.24 (d, J=3.7 Hz, 1H), 4.19 (d, J=12.3 Hz,1H), 4.17-4.13 (m, 1H), 3.91 (d, J=12.3 Hz, 1H), 3.64 (d, J=1.0 Hz, 3H),1.26 (s, 1H), 1.18 (d, J=1.1 Hz, 9H), 1.06 (dd, J=6.2, 1.0 Hz, 3H), 0.97(d, J=1.0 Hz, 9H), 0.89 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 526 (M+H)⁺.

Example 48(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid Example 48A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-nitropyrrolidine-2-carboxylate

A solution of Core 6 (5.00 g, 14.78 mmol) and triethylamine (4.74 mL,34.0 mmol) in dichloromethane, 50 mL) at 0° C. was treated withcyclohexanecarbonyl chloride (2.57 mL, 19.21 mmol), and stirred at 0° C.for 30 minutes and at 25° C. for 1 hour. The reaction was diluted withdichloromethane (50 mL) and the mixture was washed with saturatedaqueous NaHCO₃. The organics were washed with brine, dried over MgSO₄,filtered, and concentrated. The crude material was purified by silicacolumn chromatography on silica gel eluting with petroleum ether/ethylacetate 10:1 to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-nitropyrrolidine-2-carboxylate(3.5596 g, 7.54 mmol, 51.0% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.06(td, J=7.8, 1.7 Hz, 1H), 7.61-7.49 (m, 0H), 7.33 (tdd, J=7.5, 5.4, 1.7Hz, 1H), 7.25-7.14 (m, 1H), 7.11-7.03 (m, 1H), 7.03-6.94 (m, 0H), 5.78(dd, J=17.0, 8.4 Hz, 1H), 5.43-5.33 (m, 1H), 4.93 (d, J=3.2 Hz, 1H),4.66 (d, J=1.7 Hz, 0H), 4.48-4.27 (m, 2H), 3.14-3.01 (m, 1H), 2.37 (td,J=11.4, 5.8 Hz, 0H), 1.94 (ddt, J=11.3, 6.6, 3.5 Hz, 1H), 1.85-1.76 (m,2H), 1.76-1.56 (m, 3H), 1.51 (dd, J=12.9, 3.6 Hz, 2H), 1.37 (dt, J=21.9,7.1 Hz, 3H), 1.25 (d, J=7.5 Hz, 2H), 1.08 (d, J=15.7 Hz, 9H), 0.63 (dd,J=14.9, 11.2 Hz, 1H).

Example 48B (2S,3R,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-oxopyrrolidine-2-carboxylate

Example 48A (2.227 g, 4.97 mmol) was dissolved in ethanol (75 mL) andthe solution was degassed by bubbling nitrogen through for about 20minutes. The mixture was heated to 75° C. under nitrogen. A separatesolution of CrCl₂ was prepared under nitrogen by dissolving potassiumdichromate (4.97 g, 16.88 mmol) in aqueous hydrochloric acid, 6M (75 mL)and adding Zn (8.93 g, 137 mmol) (in portions while cooling in an icebath, keeping the internal temperature around 25° C.). The color of thesolution went from dark brown to dark green to clear light blue. Thesolution bubbled steadily. The CrCl₂ solution was added via cannula over20 minutes to the solution of starting material. The reaction was warmedto 80° C. (internal temperature) and heating was continued for 19 hours.The mixture was cooled to room temperature, concentrated, diluted withwater (50 mL), and extracted with dichloromethane (3×200 mL). Theextracts were combined, dried over sodium sulfate, filtered, andconcentrated. The material was re-esterified using the followingprocedure: The crude residue was dissolved in 20 mL of ethanol. Aseparate solution of HCl/ethanol was prepared by addition of 3 mL ofacetyl chloride to 10 mL of ethanol cooled in an ice bath. The mixtureswere combined and heated to 45° C. for 1 hour, at which point all acidhad converted to the desired ester product. The mixture was concentratedin vacuo and the crude material was loaded onto a 80 g silica gel columnand eluted with 0-30% ethyl acetate/heptanes over 20 minutes to provide(2S,3R,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-oxopyrrolidine-2-carboxylate(1.041 g, 2.493 mmol, 50.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.72(d, J=8.2 Hz, 1H), 7.42-7.31 (m, 1H), 7.24-7.10 (m, 2H), 5.41 (s, 1H),4.82 (d, J=3.9 Hz, 1H), 4.25-4.12 (m, 2H), 2.66 (d, J=3.9 Hz, 1H), 2.25(s, 1H), 1.69 (d, J=11.0 Hz, 2H), 1.53 (d, J=10.9 Hz, 2H), 1.39-1.27 (m,2H), 1.22 (td, J=7.1, 0.8 Hz, 3H), 1.17-1.10 (m, 2H), 1.06 (d, J=0.8 Hz,9H), 0.96-0.76 (m, 2H); MS (ESI+) m/z 418 (M+H)⁺.

Example 48C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxylate

Example 48B (1.00 g, 2.395 mmol) was dissolved in ethanol (11.98 mL) andsodium borohydride (0.181 g, 4.79 mmol) was added after cooling thereaction to <−7° C. in an ice/acetone bath. The reaction mixture wasstirred at the same temperature for 30 minutes, concentrated andpartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organics were concentrated and the crude material waspurified on a 40 g silica gel column, eluting with 0-100% methyltert-butyl ether/heptanes over 40 minutes. The purified material wasprecipitated from ethyl acetate/hexane to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxylate(0.703 g, 1.676 mmol, 70.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.94(s, 1H), 7.35-7.20 (m, 1H), 7.16-6.97 (m, 2H), 5.29 (d, J=6.7 Hz, 1H),4.42 (t, J=4.7 Hz, 2H), 4.36 (s, 1H), 4.17 (q, J=7.1 Hz, 2H), 2.84-2.77(m, 1H), 2.29 (t, J=4.3 Hz, 1H), 2.13 (s, 1H), 1.67 (dt, J=11.0, 4.3 Hz,2H), 1.51 (d, J=9.6 Hz, 2H), 1.25 (t, J=7.1 Hz, 4H), 1.17-1.05 (m, 2H),0.99 (s, 9H), 0.91-0.67 (m, 1H); MS (APCI+) m/z 420 (M+H)⁺. Relative andabsolute stereochemistry confirmed by X-ray diffraction analysis.

Example 48D (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 48C (64 mg, 0.153 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (65 mg, 0.241mmol) were dissolved in dry dimethylformamide (0.4 mL). After cooling inan ice bath, potassium 2-methylpropan-2-olate (0.244 mL, 0.244 mmol)solution was added dropwise over 2 minutes. After 30 minutes, thereaction was acidified with 1M aqueous HCl (13 drops) and warmed to roomtemperature. The mixture was concentrated and loaded onto a 12 g silicagel column and was eluted with 5-100% methyl tert-butyl ether/heptanesover 20 minutes to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(51 mg, 0.084 mmol, 54.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31(s, 1H), 7.88 (s, 1H), 7.25-7.18 (m, 1H), 7.16 (s, 1H), 7.03 (dt,J=19.3, 8.5 Hz, 2H), 5.45 (d, J=6.2 Hz, 1H), 4.61 (d, J=3.0 Hz, 1H),4.38 (d, J=13.6 Hz, 2H), 4.17-4.01 (m, 3H), 3.89 (s, 3H), 2.53 (s, 1H),2.31-2.11 (m, 1H), 1.68 (s, 2H), 1.53 (s, 2H), 1.34-1.22 (m, 2H), 1.15(t, J=7.1 Hz, 3H), 1.12-1.06 (m, 2H), 1.02 (s, 9H), 0.89-0.80 (m, 2H);MS (APCI+) m/z 609 (M+H)⁺.

Example 48E(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid

Example 48D (51 mg, 0.084 mmol) was dissolved in methanol (0.5 mL).Lithium hydroxide (26 mg, 1.086 mmol) and water (0.500 mL) were addedand a precipitate formed. Tetrahydrofuran (0.500 mL) was added andeverything dissolved. The reaction was warmed at 45° C. overnight. Thesolvent was removed, and the reaction was acidified with 1M aqueous HCl(30 drops). The crude material was loaded onto a 12 g silica gel columnand was eluted with an ethyl acetate/ethanol/heptanes solvent systemover 20 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylicacid (41 mg, 0.071 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.29 (d, J=2.3 Hz, 1H), 8.16-8.01 (m, 1H), 7.25-7.10 (m, 2H), 7.09-6.91(m, 2H), 5.44 (d, J=6.4 Hz, 1H), 4.53-4.45 (m, 1H), 4.40 (d, J=13.8 Hz,1H), 4.34-4.28 (m, 1H), 4.06 (d, J=13.8 Hz, 1H), 3.90 (s, 3H), 2.62 (s,1H), 2.40-2.17 (m, 1H), 1.68 (d, J=10.5 Hz, 2H), 1.54 (s, 2H), 1.25 (d,J=4.2 Hz, 2H), 1.14 (d, J=19.4 Hz, 2H), 1.01 (s, 9H), 0.90-0.80 (m, 2H);MS (APCI+) m/z 581 (M+H)⁺.

Example 49(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described forExample 48 substituting2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine in Example 48D. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.05 (s, 1H), 7.44 (dd, J=8.8, 2.4 Hz, 1H),7.18 (d, J=6.8 Hz, 1H), 7.10-6.89 (m, 4H), 5.44 (d, J=6.5 Hz, 1H), 4.48(d, J=3.0 Hz, 1H), 4.40 (d, J=13.1 Hz, 1H), 4.30-4.24 (m, 1H), 4.08 (d,J=13.2 Hz, 1H), 3.77 (s, 3H), 2.60 (s, 1H), 2.40-2.15 (m, 1H), 1.77-1.64(m, 2H), 1.60-1.48 (m, 2H), 1.34-1.21 (m, 2H), 1.19-1.06 (m, 2H), 1.00(s, 9H), 0.91-0.81 (m, 2H); MS (APCI+) m/z 580 (M+H)⁺.

Example 50(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid Example 50A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylate

Example 48C (60 mg, 0.143 mmol) and2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (45 mg, 0.175 mmol) weredissolved in dry dimethylformamide (0.4 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (0.229 mL, 0.229 mmol) solutionwas added dropwise over 2 minutes. After 30 minutes, the reaction wasacidified with 1M aqueous HCl (10 drops) and warmed to room temperature.The mixture was concentrated and loaded onto a 12 g silica gel columnand was eluted with 5-100% methyl tert-butyl ether/heptanes over 20minutes to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylate(72 mg, 0.121 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.94 (s,1H), 7.23 (d, J=7.2 Hz, 1H), 7.13 (dd, J=8.6, 2.6 Hz, 1H), 7.06 (dt,J=18.6, 8.6 Hz, 2H), 6.83 (d, J=2.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H),5.44 (d, J=6.3 Hz, 1H), 4.54 (d, J=3.4 Hz, 1H), 4.33-4.24 (m, 2H), 4.08(qd, J=7.0, 1.2 Hz, 2H), 4.02 (d, J=12.1 Hz, 1H), 3.64 (s, 3H), 2.50 (s,1H), 2.25-2.10 (m, 1H), 1.68 (d, J=8.2 Hz, 2H), 1.52 (s, 2H), 1.32-1.19(m, 2H), 1.17 (s, 9H), 1.14 (t, J=7.1 Hz, 3H), 1.11-1.04 (m, 2H), 0.97(s, 9H), 0.90-0.76 (m, 2H); MS (APCI+) m/z 596 (M+H)⁺.

Example 50B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid

Example 50A (70 mg, 0.117 mmol) was dissolved in methanol (0.5 mL).Lithium hydroxide (26 mg, 1.086 mmol) and water (0.500 mL) were addedand a precipitate formed. Tetrahydrofuran (0.500 mL) was added andeverything dissolved. The reaction was warmed at 45° C. overnight. Thesolvent was removed, and the reaction was acidified with 1M aqueous HCl(30 drops). The crude material was loaded onto a 12 g silica gel columnand was eluted with an ethyl acetate/ethanol/heptanes solvent systemover 20 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid (46 mg, 0.081 mmol, 69.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.08 (s, 1H), 7.20 (d, J=6.2 Hz, 1H), 7.13 (dd, J=8.6, 2.6 Hz, 1H),7.10-6.96 (m, 2H), 6.85 (d, J=2.5 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 5.43(d, J=6.6 Hz, 1H), 4.44 (d, J=3.4 Hz, 1H), 4.28 (d, J=12.3 Hz, 1H), 4.23(d, J=7.2 Hz, 1H), 4.03 (d, J=12.3 Hz, 1H), 3.65 (s, 3H), 2.56 (s, 1H),2.27 (d, J=21.7 Hz, 1H), 1.68 (d, J=7.8 Hz, 2H), 1.53 (s, 2H), 1.34-1.21(m, 2H), 1.17 (d, J=0.8 Hz, 9H), 1.15-1.06 (m, 2H), 0.96 (s, 9H),0.91-0.79 (m, 2H); MS (APCI+) m/z 568 (M+H)⁺.

Example 51(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid Example 51A (2S,3R,4S,5S)-ethyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylate

Example 48C (273 mg, 0.651 mmol) and5-bromo-3-(bromomethyl)-2-methoxypyridine (273 mg, 0.972 mmol) weredissolved in dry dimethylformamide (2.0 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (1.041 mL, 1.041 mmol) solutionwas added dropwise over 2 minutes. After 30 minutes, the reaction wasacidified with 1M aqueous HCl (20 drops) and warmed to ambienttemperature. The crude material was concentrated and loaded onto a 24 gsilica gel column and was eluted with 5-100% methyl tert-butylether/heptanes over 25 minutes to provide (2S,3R,4S,5S)-ethyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylate(0.373 g, 0.602 mmol, 93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.02(d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.26 (d, J=6.7 Hz, 1H), 7.12 (d, J=7.5Hz, 1H), 7.04 (dd, J=10.7, 8.4 Hz, 1H), 6.97 (s, 1H), 5.44 (d, J=6.2 Hz,1H), 4.60 (d, J=2.9 Hz, 1H), 4.30 (d, J=13.6 Hz, 2H), 4.13 (qd, J=7.1,2.9 Hz, 2H), 4.02-3.95 (m, 1H), 3.79 (s, 3H), 2.51 (s, 1H), 2.33-2.10(m, 1H), 1.68 (s, 2H), 1.53 (s, 2H), 1.26 (s, 2H), 1.18 (t, J=7.1 Hz,3H), 1.14-1.06 (m, 2H), 1.01 (s, 9H), 0.89-0.79 (m, 2H); MS (APCI+) m/z621 (M+H)⁺.

Example 51B(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid

Example 51A (33 mg, 0.053 mmol) was dissolved in methanol (0.5 mL).Lithium hydroxide (14 mg, 0.585 mmol) and water (0.500 mL) were addedand a precipitate formed. Tetrahydrofuran (0.500 mL) was added andeverything dissolved. The reaction was warmed at 45° C. overnight. Thesolvent was removed, and the reaction was acidified with 1M aqueous HCl(30 drops). The crude material was purified directly using a 12 g silicagel cartridge eluting with an ethyl acetate/ethanol/heptanes solventsystem over 20 minutes to provide(2S,3R,4S,5S)-4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid (29 mg, 0.049 mmol, 92% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.13-8.03 (m, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.29-7.17 (m, 1H), 7.13-7.04(m, 1H), 7.05-6.95 (m, 1H), 6.94 (s, 1H), 5.42 (s, 1H), 4.47 (s, 1H),4.32 (d, J=13.7 Hz, 1H), 4.27 (s, 1H), 3.99 (d, J=13.6 Hz, 1H), 3.80 (s,3H), 2.60 (s, 1H), 1.79-1.63 (m, 3H), 1.62-1.48 (m, 2H), 1.34-1.20 (m,3H), 1.20-1.04 (m, 2H), 1.01 (s, 9H), 0.93-0.79 (m, 2H); MS (APCI+) m/z580 (M+H)⁺.

Example 52(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described forExample 48 substituting 5-bromo-3-(bromomethyl)-2-methoxypyridine for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine in Example 48Dthen following the procedures described in Example 38E-38F. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.21 (d, J=2.5 Hz, 1H), 8.08 (s, 1H), 7.48-7.39 (m,4H), 7.37-7.30 (m, 1H), 7.22 (s, 1H), 7.14-7.06 (m, 1H), 7.06-6.98 (m,1H), 6.98-6.89 (m, 1H), 5.44 (d, J=6.5 Hz, 1H), 4.49 (s, 1H), 4.40 (d,J=13.3 Hz, 1H), 4.31 (s, 1H), 4.09 (d, J=13.3 Hz, 1H), 3.86 (s, 3H),2.63 (s, 1H), 1.77-1.61 (m, 3H), 1.61-1.46 (m, 2H), 1.34-1.20 (m, 2H),1.19-1.06 (m, 2H), 1.01 (s, 9H), 0.91-0.78 (m, 2H); MS (APCI+) m/z 589(M+H)⁺.

Example 53(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid Example 53A (2S,3R,4S,5S)-ethyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

The title compound was prepared according to the procedure described inExample 51A, substituting Example 41C for Example 48C. LC/MS (APCI+) m/z603.0 (M+H)⁺.

Example 53B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid

In a 4 mL vial, Example 53A (50.0 mg, 0.083 mmol, 1.0 eq) anddichloro[4,5-dichloro-1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl, 7.15 mg, 0.0083 mmol, 0.1 eq) were dissolved intetrahydrofuran (1.0 mL), flushed with nitrogen and stirred at roomtemperature. Cyclobutylzinc bromide (0.5 M, 498 μL, 0.25 mmol, 3.0 eq)was added and the reaction was stirred at room temperature for 30minutes. The solvent was removed under a stream of nitrogen, and thecrude material was reconstituted in 3:2 tetrahydrofuran/methanol (1.0mL). LiOH monohydrate (34 mg, 0.83 mmol, 10 eq) in H₂O (300 μL) wasadded and reaction was stirred overnight at 45° C. The solvent wasremoved under a stream of nitrogen. The residue was acidified with 1 Maqueous HCl and was extracted with dichloromethane (3×2 mL). The solventwas removed and the crude material was reconstituted in acetonitrile.The reaction mixture was loaded directly into an injection loop andpurified using prep LC method TFA8 to provide the title compound (23.8mg, 43.0% yield). ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm7.76 (d, J=2.5 Hz, 1H), 7.65 (d, J=7.2 Hz, 2H), 7.29-7.15 (m, 3H), 6.92(d, J=2.4 Hz, 1H), 5.19 (d, J=6.4 Hz, 1H), 4.50 (d, J=3.2 Hz, 1H),4.30-4.16 (m, 2H), 3.90 (d, J=13.1 Hz, 1H), 3.76 (s, 3H), 3.40-3.27 (m,1H), 2.29-2.19 (m, 3H), 2.03-1.80 (m, 4H), 1.67-1.60 (m, 2H), 1.50-1.45(m, 2H), 0.98 (s, 15H), 0.90-0.50 (m, 1H); MS (APCI+) m/z 549.1 (M+H)⁺.

Example 54(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid

In a 4 mL vial, Example 53A (50.0 mg, 0.083 mmol, 1.0 eq) anddichloro[4,5-dichloro-1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl, 7.15 mg, 0.0083 mmol, 0.1 eq) were dissolved intetrahydrofuran (1.0 mL), flushed with nitrogen, and stirred at roomtemperature. Cyclopentylzinc bromide (0.5 M, 498 μL, 0.25 mmol, 3.0 eq)was added and reaction was stirred at room temperature for 30 minutes.The solvent was removed under a stream of nitrogen, and the crudematerial was reconstituted in 3:2 tetrahydrofuran/methanol (1.0 mL).LiOH monohydrate (34 mg, 0.83 mmol, 10 eq) in H₂O (300 μL) was added andreaction was stirred overnight at 45° C. The solvent was removed under astream of nitrogen. The residue was acidified with 1 M aqueous HCl andextracted with dichloromethane (3×2 mL). The solvent was removed and thecrude material was reconstituted in acetonitrile. The reaction wasloaded directly into an injection loop and purified using prep LC methodTFA8 to provide the title compound (36.0 mg, 64.0% yield). ¹H NMR (400MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 7.78 (d, J=2.4 Hz, 1H), 7.64(d, J=7.3 Hz, 2H), 7.28-7.13 (m, 3H), 6.90 (d, J=2.4 Hz, 1H), 5.19 (d,J=6.3 Hz, 1H), 4.49 (d, J=3.3 Hz, 1H), 4.25-4.16 (m, 2H), 3.90 (d,J=13.0 Hz, 1H), 3.76 (s, 3H), 2.88-2.74 (m, 1H), 2.50-2.46 (m, 1H),2.29-2.13 (m, 1H), 1.95-1.87 (m, 2H), 1.81-1.70 (m, 2H), 1.68-1.59 (m,4H), 1.50-1.45 (m, 2H), 1.46-1.30 (m, 2H), 1.27-1.03 (m, 5H), 0.98 (s,9H), 0.81-0.56 (m, 1H); MS (APCI+) m/z 563.1 (M+H)⁺.

Example 55(2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid

In a 4 mL vial, Example 53A (50.0 mg, 0.083 mmol, 1.0 eq) anddichloro[4,5-dichloro-1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl, 7.15 mg, 0.0083 mmol, 0.1 eq) were dissolved intetrahydrofuran (1.0 mL), flushed with nitrogen and stirred at roomtemperature. exo-2-Norbornylzinc bromide (0.5 M, 498 μL, 0.25 mmol, 3.0eq) was added and reaction was stirred at room temperature for 30minutes. The solvent was removed under a stream of nitrogen, andreconstituted in 3:2 tetrahydrofuran/methanol (1.0 mL). LiOH monohydrate(34 mg, 0.83 mmol, 10 eq) in H₂O (300 μL) was added and reaction wasstirred overnight at 45° C. The solvent was removed under a stream ofnitrogen. The residue was acidified with 1 M aqueous HCl and wasextracted with dichloromethane (3×2 mL). The solvent was removed and thecrude material was reconstituted in acetonitrile. The reaction mixturewas loaded directly into an injection loop and purified using prep LCmethod TFA8 to provide the title compound (25.9 mg, 44% yield). ¹H NMR(400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 7.80-7.73 (m, 1H),7.67-7.61 (m, 2H), 7.29-7.10 (m, 3H), 6.94-6.84 (m, 1H), 5.19 (d, J=6.4Hz, 1H), 4.51-4.44 (m, 1H), 4.28-4.16 (m, 2H), 3.94-3.86 (m, 1H),3.79-3.73 (m, 3H), 3.01-2.93 (m, 1H), 2.49 (s, 1H), 2.35-2.08 (m, 3H),1.68-1.60 (m, 2H), 1.60-1.36 (m, 5H), 1.34-1.03 (m, 9H), 1.00-0.95 (m,10H), 0.88-0.54 (m, 1H); MS (APCI+) m/z 589.1 (M+H)⁺.

Example 56(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 53, substituting Example 51A for Example 53A. ¹H NMR (400 MHz,120° C., DMSO-d₆:D₂O=9:1 (v/v)) 6 ppm 7.97-7.92 (m, 1H), 7.77 (d, J=2.4Hz, 1H), 7.27-7.22 (m, 1H), 7.12-6.98 (m, 2H), 6.89 (s, 1H), 5.42 (d,J=6.3 Hz, 1H), 4.54 (d, J=2.9 Hz, 1H), 4.34-4.20 (m, 2H), 4.00 (d,J=13.0 Hz, 1H), 3.77 (s, 3H), 3.39-3.26 (m, 1H), 2.54 (s, 1H), 2.23 (s,2H), 2.02-1.80 (m, 4H), 1.74-1.60 (m, 2H), 1.58-1.45 (m, 2H), 1.32-1.04(m, 5H), 1.01-0.96 (m, 10H), 0.86-0.67 (m, 1H); MS (APCI+) m/z 567.1(M+H)⁺.

Example 57(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 54, substituting Example 51A for Example 53A. ¹H NMR (400 MHz,120° C., DMSO-d₆:D₂O=9:1 (v/v)) 6 ppm 7.93 (s, 1H), 7.79 (d, J=2.5 Hz,1H), 7.26-7.19 (m, 1H), 7.11-6.98 (m, 2H), 6.90-6.85 (m, 1H), 5.42 (d,J=6.3 Hz, 1H), 4.53 (d, J=2.9 Hz, 1H), 4.34-4.21 (m, 2H), 3.99 (d,J=13.0 Hz, 1H), 3.76 (s, 3H), 2.87-2.73 (m, 1H), 2.53 (s, 1H), 2.17 (s,1H), 1.91-1.86 (m, 2H), 1.80-1.59 (m, 6H), 1.55-1.50 (m, 2H), 1.43-1.03(m, 7H), 0.98 (s, 9H), 0.88-0.59 (m, 1H); MS (APCI+) m/z 581.1 (M+H)⁺.

Example 58(2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 55, substituting Example 51A for Example 53A. ¹H NMR (400 MHz,120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.00-7.89 (m, 1H), 7.82-7.73 (m,1H), 7.25-7.20 (m, 1H), 7.10-7.00 (m, 2H), 6.87 (d, J=17.2 Hz, 1H), 5.42(d, J=6.2 Hz, 1H), 4.55-4.48 (m, 1H), 4.34-4.19 (m, 2H), 4.04-3.94 (m,1H), 3.80-3.74 (m, 3H), 3.04-2.90 (m, 1H), 2.53 (s, 1H), 2.34-2.06 (m,3H), 1.78-1.59 (m, 3H), 1.59-0.92 (m, 23H), 0.82 (s, 1H); MS (APCI+) m/z607.1 (M+H)⁺.

Example 59(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid

In a 4 mL vial, (2S,3R,4S,5S)-ethyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylate(Example 51A, 0.050 g, 0.081 mmol), sodium tert-butoxide (0.039 g, 0.404mmol), and RuPhos palladacycle (0.012 g, 0.016 mmol) were treated withdioxane (1.6 mL) and pyrrolidine (0.01 mL, 0.121 mmol). The vial wassealed with a screw cap, and the reaction was placed in a preheatedheating block and stirred at 85° C. overnight. The reaction mixture wasthen concentrated in vacuo, and the residue was purified byreverse-phase HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acidin water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A,1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 minlinear gradient 95-5% A) to provide the title compound, 0.0024 g (5%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.98 (s, 1H), 7.30-7.16 (m, 2H),7.04 (m, 2H), 6.45 (d, J=3.0 Hz, 1H), 5.42 (m, 1H), 4.54 (d, J=2.9 Hz,1H), 4.29-4.26 (m, 2H), 4.04-3.92 (m, 1H), 3.71 (s, 3H), 3.05 (m, 4H),2.55 (m, 1H), 2.20 (m, 1H), 1.93 (m, 4H), 1.75-1.06 (m, 10H), 1.00 (s,9H); MS (ESI⁺) m/z 582.1 (M+H)⁺.

Example 60(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 41D, substituting3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.94 (d, J=3.5 Hz, 1H), 7.68 (d, J=7.5 Hz, 2H), 7.30-7.10(m, 4H), 5.21 (d, J=6.4 Hz, 1H), 4.47 (d, J=3.5 Hz, 1H), 4.23 (dd,J=11.2, 5.5 Hz, 2H), 3.91 (d, J=13.0 Hz, 1H), 3.77 (s, 3H), 2.5 (m, 1H),2.24 (s, 1H), 1.65 (d, J=9.8 Hz, 2H), 1.49 (s, 2H), 1.25 (d, J=10.0 Hz,2H), 1.21 (s, 9H), 1.08 (td, J=10.1, 9.5, 4.0 Hz, 3H), 0.99 (s, 9H),0.87-0.82 (m, 1H); MS (ESI−) m/z 549.3 (M−H)⁻.

Example 61(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 31 substituting 3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridinefor 2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene in Example 31D.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.93 (d, J=2.7 Hz, 1H), 7.69 (d, J=7.4Hz, 2H), 7.21 (t, J=7.1 Hz, 2H), 7.15 (d, J=2.8 Hz, 2H), 5.15 (d, J=6.6Hz, 1H), 4.41 (s, 1H), 4.23 (d, J=13.0 Hz, 1H), 3.97-3.87 (m, 1H), 3.78(s, 3H), 3.44 (s, 1H), 3.20 (s, 3H), 2.73-2.61 (m, 1H), 2.56 (s, 1H),1.85-1.72 (m, 1H), 1.68-1.56 (m, 1H), 1.48-1.38 (m, 1H), 1.28-1.24 (m,2H), 1.20 (s, 9H), 1.19-1.04 (m, 2H), 0.99 (s, 9H), 0.89-0.78 (m, 2H);MS (APCI+) m/z 581 (M+H)⁺.

Example 62(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described forExample 48 substituting 3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridinefor 3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine in Example48D. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.20 (s, 1H), 7.94 (d, J=2.7 Hz,1H), 7.18 (s, 1H), 7.12 (s, 1H), 7.02 (s, 2H), 5.45 (s, 1H), 4.40 (s,1H), 4.30 (d, J=13.0 Hz, 1H), 4.24 (s, 1H), 4.11-3.99 (m, 1H), 3.78 (s,3H), 2.65 (s, 1H), 1.68 (d, J=11.2 Hz, 2H), 1.55 (s, 2H), 1.29-1.23 (m,3H), 1.18 (s, 9H), 1.15-1.07 (m, 2H), 0.98 (s, 9H), 0.89-0.81 (m, 2H);MS (APCI+) m/z 569 (M+H)⁺.

Example 63(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described forExample 38A-38D and Example 38F substituting3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine for4-bromo-2-(bromomethyl)-1-methoxybenzene in Example 38D. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.93 (d, J=2.6 Hz, 1H), 7.70-7.65 (m, 2H), 7.21-7.06(m, 4H), 4.98 (d, J=6.6 Hz, 1H), 4.62 (p, J=6.2 Hz, 1H), 4.24-4.18 (m,2H), 4.16 (dd, J=6.7, 3.2 Hz, 1H), 3.93-3.87 (m, 1H), 3.77 (s, 3H), 2.55(t, J=3.4 Hz, 1H), 1.20 (s, 9H), 1.07 (d, J=6.2 Hz, 3H), 0.98 (s, 9H),0.88 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 527 (M+H)⁺.

Example 64(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 64A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38C (37 mg, 0.098 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (47.6 mg, 0.176mmol) were dissolved in dry dimethylformamide (0.5 mL). After cooling inan ice bath, potassium 2-methylpropan-2-olate (0.157 mL, 0.157 mmol)solution was added dropwise over 2 minutes. LC/MS showed desiredproduct. The mixture was acidified with 1M aqueous HCl (10 drops) andwarmed to room temperature. The mixture was concentrated and loaded ontoa 12 g silica gel column and eluted with 5-100% ethyl acetate/heptanesover 20 minutes to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate(52 mg, 0.092 mmol, 94% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.28 (s,1H), 7.58-7.53 (m, 2H), 7.22 (d, J=2.3 Hz, 1H), 7.17 (dd, J=8.2, 6.6 Hz,2H), 7.13-7.07 (m, 1H), 5.02 (d, J=6.1 Hz, 1H), 4.64 (pd, J=6.2, 0.9 Hz,1H), 4.37 (d, J=3.1 Hz, 1H), 4.30-4.24 (m, 2H), 4.16-4.03 (m, 2H), 3.87(d, J=0.9 Hz, 3H), 2.87-2.81 (m, 2H), 1.15 (td, J=7.1, 0.9 Hz, 3H), 1.05(d, J=6.2 Hz, 3H), 1.01 (d, J=0.9 Hz, 9H), 0.90 (d, J=6.2 Hz, 3H); MS(APCI+) m/z 567 (M+H)⁺.

Example 64B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 64A (52 mg, 0.092 mmol) was dissolved in methanol (0.5 mL) and a2M aqueous solution of lithium hydroxide (0.459 mL, 0.918 mmol) wasadded. The reaction was warmed at 45° C. overnight, acidified with 2Maqueous HCl (0.460 mL), and concentrated. The residue was loaded onto a12 g silica gel column and eluted with 5-100% ethylacetate/ethanol/heptanes over 20 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-1-(isopropoxycarbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenylpyrrolidine-2-carboxylicacid (22 mg, 0.041 mmol, 44.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.68-7.62 (m, 2H), 7.20-7.16 (m, 2H), 7.16-7.12 (m, 2H), 7.13-7.05 (m,1H), 5.00 (d, J=6.5 Hz, 1H), 4.63 (p, J=6.2 Hz, 1H), 4.30 (d, J=14.0 Hz,1H), 4.26 (d, J=3.1 Hz, 1H), 4.21 (dd, J=6.5, 2.5 Hz, 1H), 3.93 (d,J=13.9 Hz, 1H), 3.88 (s, 3H), 2.55 (t, J=2.8 Hz, 1H), 1.06 (d, J=6.2 Hz,3H), 1.00 (s, 9H), 0.89 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 539 (M+H)⁺.

Example 65(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluoro-4-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 40A (25 mg, 0.043 mmol, 1.0 eq) and PdCl₂(dppf)([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 3.2 mg,0.0043 mmol, 0.1 eq) suspended in 500 μL dioxane was placed under anitrogen atmosphere. (2-Fluoro-4-methylphenyl)boronic acid (0.4 M, 215μL, 0.086 mmol, 2.0 eq) was added and the mixture was stirred at roomtemperature for 5 minutes. Cs₂CO₃ (1 M, 129 μL, 0.129 mmol, 3.0 eq) wasadded and reaction mixture was heated to 100° C. for 1 hour. The solventwas removed under a stream of nitrogen, and the residue wasreconstituted in 500 μL 3:2 tetrahydrofuran/methanol. LiOH monohydrate(20 mg/100 uL) was added and reaction was stirred at 45° C. overnight.The solvent was removed under a stream of nitrogen. The residue wasacidified with 1 M aqueous HCl and extracted with dichloromethane (3×1mL). The reaction was loaded directly into an injection loop andpurified using prep LC method TFA8 to provide the title compound (12.8mg, 33% yield). ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm8.10-8.04 (m, 1H), 7.53 (d, J=7.5 Hz, 2H), 7.22-6.95 (m, 7H), 4.97 (d,J=6.3 Hz, 1H), 4.62 (p, J=6.2 Hz, 1H), 4.31 (d, J=3.1 Hz, 1H), 4.26 (d,J=13.2 Hz, 1H), 4.20 (dd, J=6.2, 2.5 Hz, 1H), 3.93 (d, J=13.1 Hz, 1H),3.83 (s, 3H), 2.49-2.45 (m, 1H), 2.37 (s, 3H), 1.04 (d, J=6.2 Hz, 3H),0.99 (s, 9H), 0.87 (d, J=6.1 Hz, 3H); MS (APCI+) m/z 579.0 (M+H)⁺.

Example 66(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 65 substituting2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for(2-fluoro-4-methylphenyl)boronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.09 (s, 1H), 7.53 (d, J=7.9 Hz, 2H),7.44-7.36 (m, 1H), 7.34-7.19 (m, 3H), 7.17-7.11 (m, 1H), 7.08 (t, J=7.6Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.97 (d, J=6.3 Hz, 1H), 4.62 (p, J=6.3Hz, 1H), 4.31 (d, J=3.1 Hz, 1H), 4.27 (d, J=13.3 Hz, 1H), 4.21 (dd,J=6.3, 2.4 Hz, 1H), 3.95 (d, J=13.3 Hz, 1H), 3.84 (s, 3H), 2.50-2.46 (m,1H), 1.04 (d, J=6.2 Hz, 3H), 0.99 (s, 9H), 0.87 (d, J=6.2 Hz, 3H); MS(APCI+) m/z 565.1 (M+H)⁺.

Example 67(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(4-fluoro-2-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 65 substituting2-(4-fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for(2-fluoro-4-methylphenyl)boronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 7.86-7.80 (m, 1H), 7.54-7.47 (m, 2H),7.12-6.97 (m, 5H), 6.97-6.89 (m, 1H), 6.89-6.84 (m, 1H), 4.96 (d, J=6.1Hz, 1H), 4.61 (hept, J=6.0 Hz, 1H), 4.30 (d, J=3.1 Hz, 1H), 4.27 (d,J=13.5 Hz, 1H), 4.19 (dd, J=6.3, 2.4 Hz, 1H), 3.96-3.89 (m, 1H), 3.83(s, 3H), 2.46 (s, 1H), 2.10 (s, 3H), 1.04 (d, J=6.2 Hz, 3H), 0.99 (s,9H), 0.87 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 579.0 (M+H)⁺.

Example 68(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2,4-difluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 65 substituting2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for(2-fluoro-4-methylphenyl)boronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.09-8.00 (m, 1H), 7.53 (d, J=7.8 Hz, 2H),7.38-7.27 (m, 1H), 7.21-7.04 (m, 5H), 7.02-6.94 (m, 1H), 4.97 (d, J=6.2Hz, 1H), 4.61 (h, J=6.3 Hz, 1H), 4.32 (d, J=3.1 Hz, 1H), 4.27 (d, J=13.1Hz, 1H), 4.20 (dd, J=6.3, 2.2 Hz, 1H), 3.94 (d, J=13.4 Hz, 1H), 3.84 (s,3H), 2.49-2.45 (m, 1H), 1.04 (d, J=6.2 Hz, 3H), 0.99 (s, 9H), 0.87 (d,J=6.2 Hz, 3H); MS (APCI+) m/z 583.0 (M+H)⁺.

Example 69(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 65 substituting2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor (2-fluoro-4-methylphenyl)boronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 7.96 (d, J=2.6 Hz, 1H), 7.60-7.52 (m, 2H),7.22-7.05 (m, 4H), 5.97-5.90 (m, 1H), 4.97 (d, J=6.2 Hz, 1H), 4.63(hept, J=12.5 Hz, 1H), 4.32 (d, J=3.0 Hz, 1H), 4.26-4.16 (m, 4H), 3.88(d, J=12.7 Hz, 1H), 3.85-3.76 (m, 5H), 2.48-2.46 (m, 1H), 2.34-2.26 (m,2H), 1.05 (d, J=6.2 Hz, 3H), 0.99 (s, 9H), 0.88 (d, J=6.2 Hz, 3H); MS(APCI+) m/z 533.1 (M+H)⁺.

Example 70(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 65 substituting2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for(2-fluoro-4-methylphenyl)boronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.19 (d, J=2.6 Hz, 1H), 7.61-7.54 (m, 2H),7.41-7.30 (m, 1H), 7.28 (d, J=2.6 Hz, 1H), 7.14 (t, J=7.5 Hz, 2H),7.10-6.97 (m, 3H), 6.93 (ddd, J=8.3, 2.5, 0.9 Hz, 1H), 4.99 (d, J=6.2Hz, 1H), 4.63 (p, J=6.1 Hz, 1H), 4.33 (d, J=3.1 Hz, 1H), 4.28 (d, J=13.2Hz, 1H), 4.23 (dd, J=6.2, 2.4 Hz, 1H), 3.98-3.91 (m, 1H), 3.85 (s, 3H),3.84 (s, 3H), 2.56-2.50 (m, 1H), 1.05 (d, J=6.2 Hz, 3H), 0.97 (s, 9H),0.88 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 577.0 (M+H)⁺.

Example 71(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(4-methylphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 65 substituting4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane for(2-fluoro-4-methylphenyl)boronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.16 (d, J=2.5 Hz, 1H), 7.61-7.54 (m, 2H),7.36-7.29 (m, 2H), 7.29-7.20 (m, 3H), 7.14 (d, J=7.8 Hz, 2H), 7.11-7.03(m, 1H), 5.00 (d, J=6.2 Hz, 1H), 4.64 (h, J=6.1 Hz, 1H), 4.33 (d, J=3.0Hz, 1H), 4.28 (d, J=13.2 Hz, 1H), 4.23 (dd, J=6.2, 2.3 Hz, 1H), 3.95 (d,J=13.6 Hz, 1H), 3.83 (s, 3H), 2.52-2.50 (m, 1H), 2.37-2.32 (m, 3H), 1.05(d, J=6.2 Hz, 3H), 1.00 (s, 9H), 0.88 (d, J=6.2 Hz, 3H); MS (APCI+) m/z561.0 (M+H)⁺.

Example 72(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described forExample 38A-38D and Example 38F substituting3-(bromomethyl)-6-(tert-butyl)-2-methoxypyridine for4-bromo-2-(bromomethyl)-1-methoxybenzene in Example 38D. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.60-7.54 (m, 2H), 7.23-7.07 (m, 3H), 6.96-6.90 (m,1H), 6.69 (d, J=7.6 Hz, 1H), 4.95 (d, J=6.3 Hz, 1H), 4.62 (p, J=6.2 Hz,1H), 4.26 (d, J=3.3 Hz, 1H), 4.17-4.08 (m, 2H), 3.84 (dd, J=12.9, 1.0Hz, 1H), 3.78 (s, 3H), 2.45-2.41 (m, 1H), 1.24 (s, 9H), 1.05 (d, J=6.2Hz, 3H), 0.97 (s, 9H), 0.88 (d, J=6.3 Hz, 3H); MS (ESI+) m/z 527 (M+H)⁺.

Example 73(2S,3R,4S,5S)-3-tert-butyl-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 73A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-nitropyrrolidine-1,2-dicarboxylate

Core 6 (1.042 g, 3.08 mmol) was dissolved in toluene (6.16 mL) andtriethylamine (1.073 mL, 7.70 mmol) was added, followed by the slowaddition of isopropyl carbonochloridate (1.848 mL, 3.70 mmol) solutionafter cooling in an ice-water bath to ˜10° C. The addition was at such arate that the temperature was maintained at or below room temperatureduring the addition (2-3 minutes). After the addition was complete, thereaction mixture was removed from the water bath and stirred at roomtemperature for 45 minutes. The mixture was diluted with ethyl acetateand stirred with saturated aqueous sodium bicarbonate for 20 minutes.The layers were separated, and the organic layer was washed with 1Maqueous HCl and brine, dried over sodium sulfate, filtered andconcentrated. The crude material was purified using a 40 g silica gelcartridge with a gradient of 5-100% ethyl acetate/heptanes over 40minutes to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-nitropyrrolidine-1,2-dicarboxylate(1.176 g, 2.77 mmol, 90% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.81(td, J=7.7, 1.8 Hz, 1H), 7.34-7.24 (m, 1H), 7.16-6.99 (m, 2H), 5.66 (d,J=8.8 Hz, 1H), 5.55 (dd, J=8.8, 3.6 Hz, 1H), 4.68 (dt, J=12.5, 6.2 Hz,1H), 4.50 (d, J=4.1 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.10-3.02 (m, 1H),1.29 (t, J=7.1 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H), 1.01 (s, 9H), 0.93 (d,J=6.2 Hz, 3H); MS (ESI+) m/z 425 (M+H)⁺.

Example 73B (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 73A (1.080 g, 2.54 mmol) was dissolved in ethanol (22 mL) andthe solution was heated to 75° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (2.393 g, 6.36 mmol) in 6Maqueous hydrochloric acid (22 mL) and adding Zn (2.39 g, 6.36 mmol) (inportions while cooling in an ice bath-large exotherms). The suspensionwas stirred at room temperature for 30 minutes after removing from theice bath, and the solution remained cloudy. Additional 6M aqueoushydrochloric acid (22 mL) was added and the suspension was stirred foranother 30 minutes, resulting in a clear brilliant blue solution. TheCrCl₂ solution was transferred via cannula/addition funnel over 20minutes to the solution of starting material, and the mixture was heatedfor 16 hours, and allowed to cool to room temperature. The mixture waspoured into a separatory funnel and extracted with 3×250 mL ofdichloromethane. The solvent was removed in vacuo and the crude materialwas chromatographed using a 40 g silica gel cartridge with a gradient of5-100% ethyl acetate/heptanes to provide (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxylate(0.409 g, 1.040 mmol, 40.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64(td, J=7.6, 1.8 Hz, 1H), 7.32 (tdd, J=7.3, 5.3, 1.8 Hz, 1H), 7.21-7.02(m, 2H), 5.16 (s, 1H), 4.73 (hept, J=5.9 Hz, 1H), 4.62 (d, J=4.2 Hz,1H), 4.19 (qd, J=7.1, 1.6 Hz, 2H), 2.64 (dd, J=4.3, 1.0 Hz, 1H), 1.22(t, J=7.1 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H), 1.06 (s, 9H), 0.97 (d, J=6.3Hz, 3H); MS (APCI+) m/z 394 (M+H)⁺.

Example 73C (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 73B (0.411 g, 1.045 mmol) was dissolved in ethanol (5.22 mL) andsodium borohydride (0.079 g, 2.089 mmol) was added after cooling themixture to <−60° C. in a dry ice-acetone bath. The ice bath was removedand the reaction was to warm to room temperature over 20 minutes. Thereaction mixture was concentrated then partitioned between ethyl acetateand saturated sodium bicarbonate. The organics were concentrated andpurified on a 40 g silica gel cartridge, eluting with 0-100% methyltert-butyl ether/heptanes over 40 minutes to provide(2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate(0.345 g, 0.872 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.86(td, J=7.8, 1.8 Hz, 1H), 7.19 (tdd, J=7.6, 5.3, 1.9 Hz, 1H), 7.10-7.04(m, 1H), 6.99 (ddd, J=10.6, 8.1, 1.2 Hz, 1H), 5.12 (d, J=6.6 Hz, 1H),4.64 (p, J=6.2 Hz, 1H), 4.41-4.34 (m, 1H), 4.26 (s, 1H), 4.16 (q, J=7.1Hz, 3H), 2.26 (t, J=4.1 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H), 1.05 (d, J=6.2Hz, 3H), 0.98 (d, J=3.0 Hz, 9H), 0.91 (d, J=6.2 Hz, 3H); MS (APCI+) m/z396 (M+H)⁺.

Example 73D (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 73C (75 mg, 0.190 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (68 mg, 0.252mmol) were dissolved in dry dimethylformamide (948 μL). After cooling inan ice bath, potassium 2-methylpropan-2-olate (303 μL, 0.303 mmol)solution was added dropwise over 2 minutes. LC/MS showed desiredproduct. The mixture was acidified with 1M aqueous HCl (10 drops) andwarmed to room temperature. The mixture was diluted with water (2 mL)and extracted with dichloromethane. The organic extracts were loadedonto a 25 g silica gel column and eluted with 5-100% ethylacetate/heptanes over 20 minutes to provide (2S,3R,4S,5S)-2-ethyl1-isopropyl3-(tert-butyl)-5-(2-fluorophenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate(72 mg, 0.123 mmol, 64.9% yield). MS (APCI+) m/z 584 (M+H)⁺.

Example 73E(2S,3R,4S,5S)-3-tert-butyl-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a solution of Example 73D (52 mg, 0.089 mmol) in tetrahydrofuran (222μL) and methanol (222 μL) was added lithium hydroxide (23 mg, 0.960mmol) and the reaction was heated at 45° C. overnight. The solvent wasremoved under a stream of nitrogen. The crude material was acidifiedwith 2M aqueous HCl (480 uL) and was purified using a 12 g silica gelcolumn eluting with an ethyl acetate/ethanol/heptanes solvent system toprovide(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-fluorophenyl)-1-(isopropoxycarbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylicacid (18.7 mg, 0.034 mmol, 37.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.29 (s, 1H), 8.12 (t, J=7.7 Hz, 1H), 7.20-7.09 (m, 2H), 7.01 (t, J=7.5Hz, 1H), 6.97-6.86 (m, 1H), 5.27 (d, J=6.5 Hz, 1H), 4.67-4.61 (m, 1H),4.38 (d, J=13.9 Hz, 1H), 4.31 (d, J=2.9 Hz, 1H), 4.26 (dd, J=6.6, 2.0Hz, 1H), 4.07-3.99 (m, 2H), 3.89 (s, 3H), 2.57 (d, J=2.5 Hz, 1H), 1.07(d, J=6.3 Hz, 3H), 1.00 (s, 9H), 0.91 (d, J=6.2 Hz, 3H); MS (APCI+) m/z557 (M+H)⁺.

Example 74(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 74A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxypyridin-3-yl)methoxy)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylateand Example 74B (2S,3R,4R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxypyridin-3-yl)methoxy)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylate

The title compound was prepared using the procedure described forExample 73D substituting3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine but subjecting theproduct to reverse phase chromatography to provide two diastereomers,the major diastereomer identified as (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxypyridin-3-yl)methoxy)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.94 (d, J=2.7 Hz, 1H), 7.89 (td, J=7.7,1.8 Hz, 1H), 7.18 (tdd, J=7.6, 5.3, 1.8 Hz, 1H), 7.14-7.11 (m, 1H),7.09-6.93 (m, 2H), 5.27 (d, J=6.2 Hz, 1H), 4.66 (p, J=6.2 Hz, 1H), 4.39(d, J=3.1 Hz, 1H), 4.31-4.23 (m, 2H), 4.09 (qd, J=7.1, 1.5 Hz, 2H), 3.96(d, J=12.8 Hz, 1H), 3.76 (s, 3H), 1.19 (s, 9H), 1.13 (t, J=7.1 Hz, 3H),1.06 (d, J=6.3 Hz, 3H), 0.99 (s, 9H), 0.91 (d, J=6.2 Hz, 3H); MS (ESI+)m/z 573 (M+H)⁺. The minor diastereomer Example 74B was identified as(2S,3R,4R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxypyridin-3-yl)methoxy)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.09 (d, J=2.7 Hz, 1H), 7.98 (td, J=8.0,1.7 Hz, 1H), 7.69 (d, J=2.6 Hz, 1H), 7.32 (tdd, J=7.5, 5.3, 1.7 Hz, 1H),7.22-7.11 (m, 2H), 5.25 (s, 1H), 4.77 (d, J=12.2 Hz, 1H), 4.71 (p, J=6.2Hz, 1H), 4.52 (d, J=12.3 Hz, 1H), 4.35 (d, J=11.1 Hz, 1H), 4.20 (qd,J=7.1, 5.3 Hz, 2H), 4.01 (dd, J=3.7, 1.7 Hz, 1H), 3.88 (s, 3H), 2.13(dd, J=11.1, 3.7 Hz, 1H), 1.31 (d, J=7.1 Hz, 3H), 1.28 (s, 9H), 1.09 (d,J=6.2 Hz, 3H), 1.06-1.00 (m, 3H), 0.93 (s, 9H); MS (ESI+) m/z 573(M+H)⁺.

Example 74C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The major diastereomer Example 74A was treated as described in Example73 to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.18-8.08 (m, 1H), 7.93 (dd, J=2.6, 0.6 Hz, 1H), 7.20-7.11 (m, 2H),7.06-6.92 (m, 2H), 5.26 (d, J=6.5 Hz, 1H), 4.64 (p, J=6.2 Hz, 1H),4.32-4.24 (m, 2H), 4.21 (dd, J=6.4, 2.4 Hz, 1H), 3.97 (dt, J=12.9, 0.8Hz, 1H), 3.77 (s, 3H), 2.55 (t, J=2.8 Hz, 1H), 1.18 (s, 9H), 1.06 (d,J=6.2 Hz, 3H), 0.98 (s, 9H), 0.90 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 545(M+H)⁺.

Example 75(2S,3R,4R,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using Example 74B and the proceduresdescribed in Example 73E. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.42 (t, J=8.0Hz, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.26 (dt,J=7.9, 6.2 Hz, 1H), 7.15-7.05 (m, 2H), 5.21 (s, 1H), 4.75-4.60 (m, 2H),4.48 (d, J=12.4 Hz, 1H), 4.23 (d, J=10.4 Hz, 1H), 4.00-3.91 (m, 1H),3.87 (s, 3H), 2.19-2.13 (m, 1H), 1.31-1.22 (m, 12H), 1.09 (d, J=6.2 Hz,3H), 0.99 (s, 9H); MS (ESI+) m/z 545 (M+H)⁺.

Example 76(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described forExample 73E, substituting Example 77A for Example 73D. ¹H NMR (400 MHz,DMSO-d₆, 90° C.) δ ppm 8.06-7.99 (m, 2H), 7.21 (tdd, J=7.5, 5.2, 1.8 Hz,1H), 7.07 (td, J=7.5, 1.2 Hz, 1H), 7.02-6.95 (m, 1H), 6.92 (d, J=2.4 Hz,1H), 5.24 (d, J=6.3 Hz, 1H), 4.65 (p, J=6.2 Hz, 1H), 4.34-4.27 (m, 2H),4.24 (dd, J=6.4, 1.8 Hz, 1H), 3.96 (d, J=13.8 Hz, 1H), 3.78 (s, 3H),2.50 (t, J=2.2 Hz, 1H), 1.06 (d, J=6.2 Hz, 3H), 0.99 (s, 9H), 0.94-0.87(m, 3H); MS (APCI+) m/z 567 (M+H)⁺.

Example 77(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 77A (2S,3R,4S,5S)-2-ethyl 1-isopropyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylate

Example 73C (109 mg, 0.276 mmol) and5-bromo-3-(bromomethyl)-2-methoxypyridine (105 mg, 0.374 mmol) weredissolved in dry dimethylformamide (612 μL). After cooling in an icebath, potassium 2-methylpropan-2-olate (441 μL, 0.441 mmol) solution wasadded dropwise over 2 minutes. After 30 minutes, the reaction wasacidified with 1M aqueous HCl (10 drops) and warmed to room temperature.The mixture was concentrated and loaded onto a 24 g silica gel columnand was eluted with 5-50% ethyl acetate/heptanes over 40 minutes toprovide 100 mg of desired product as a mixture of diastereomers. Thematerial was rechromatographed using reverse phase HPLC (CH₃CN/H₂O/TFA)to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylate(76 mg, 0.128 mmol, 46.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.02(d, J=2.5 Hz, 1H), 7.86 (td, J=7.8, 1.8 Hz, 1H), 7.22 (tdd, J=7.5, 5.3,1.8 Hz, 1H), 7.08 (td, J=7.6, 1.1 Hz, 1H), 7.04-6.92 (m, 2H), 5.26 (d,J=6.1 Hz, 1H), 4.68 (p, J=6.2 Hz, 1H), 4.40 (d, J=2.9 Hz, 1H), 4.32-4.25(m, 2H), 4.17-4.08 (m, 2H), 3.96 (d, J=13.5 Hz, 1H), 3.79 (d, J=0.8 Hz,3H), 1.18 (td, J=7.1, 0.9 Hz, 3H), 1.07 (d, J=6.2 Hz, 3H), 1.01 (d,J=0.9 Hz, 9H), 0.95-0.91 (m, 4H); MS (ESI+) m/z 596 (M+H)⁺.

Example 77B (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylate

Example 77A (45 mg, 0.076 mmol) in tetrahydrofuran (756 μL) treated withPdCl₂(dppf) (2.76 mg, 3.78 μmol), followed by dropwise addition ofcyclobutylzinc(II) bromide (0.5M in tetrahydrofuran) (302 μL, 0.151mmol) at room temperature. The reaction was stirred at ambienttemperature for 2 hours. The reaction mixture was quenched withsaturated aqueous NH₄Cl solution and the solvent was concentrated undera stream of nitrogen. The crude product was purified using a 12 g silicagel cartridge with a gradient of 5-10% ethyl acetate/heptanes over 20minutes to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-fluorophenyl)pyrrolidine-1,2-dicarboxylate(21 mg, 0.037 mmol, 48.7% yield). MS (ESI+) m/z 552 (M+H)⁺.

Example 77C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a solution of Example 77B (21 mg, 0.037 mmol) in tetrahydrofuran (1mL) and methanol (1.000 mL) was added lithium hydroxide (0.2 mL, 0.400mmol) in water (1 mL) and the reaction was heated at 45° C. for 72hours. The solvent was removed under a stream of nitrogen. The crudematerial was acidified with 2M aqueous HCl (400 uL) and was purifiedusing a 12 g silica gel column eluting with an ethylacetate/ethanol/heptanes solvent system to provide a mixture ofcylobutyl and bromo products as identified by LC/MS. The material wasrepurified by reverse phase HPLC usingacetonitrile/water/trifluoroacetic acid to provide(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-fluorophenyl)-1-(isopropoxycarbonyl)pyrrolidine-2-carboxylicacid (7 mg, 0.013 mmol, 35.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.95 (td, J=7.8, 1.8 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.19 (tdd, J=7.6,5.3, 1.8 Hz, 1H), 7.06 (td, J=7.5, 1.2 Hz, 1H), 6.98 (ddd, J=10.8, 8.2,1.3 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 5.26 (d, J=6.3 Hz, 1H), 4.66 (p,J=6.2 Hz, 1H), 4.35 (d, J=2.9 Hz, 1H), 4.28 (d, J=13.0 Hz, 1H), 4.24(dd, J=6.2, 2.0 Hz, 1H), 3.98 (d, J=13.1 Hz, 1H), 3.76 (s, 3H),3.39-3.26 (m, 1H), 2.50 (t, J=2.6 Hz, 1H), 2.23 (ddd, J=9.0, 7.1, 3.0Hz, 2H), 2.01-1.79 (m, 4H), 1.07 (d, J=6.1 Hz, 3H), 0.99 (s, 9H), 0.91(d, J=6.2 Hz, 3H); MS (ESI+) m/z 543 (M+H)⁺.

Example 78(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 95E, substituting2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.11 (ddd, J=7.4, 2.0, 0.7 Hz, 1H), 7.90 (dd, J=4.9, 1.9Hz, 1H), 7.43 (dd, J=8.5, 2.4 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.91 (t,J=1.6 Hz, 1H), 6.78 (dd, J=7.4, 4.9 Hz, 1H), 5.27-5.20 (m, 1H), 5.18 (d,J=5.9 Hz, 1H), 4.67 (hept, J=6.2 Hz, 1H), 4.40 4.32 (m, 3H), 4.00 (d,J=13.3 Hz, 1H), 3.75 (s, 3H), 2.6 (s, 1H), 1.28 (d, J=6.1 Hz, 3H), 1.20(d, J=6.2 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.00 (s, 9H), 0.92 (d, J=6.2Hz, 3H); MS (ESI+) m/z 597.1 (M+H)⁺.

Example 79(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 79A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-nitropyrrolidine-1,2-dicarboxylate

Core 8 (2.003 g, 5.64 mmol) was dissolved in toluene (6.64 mL) andtriethylamine (1.967 mL, 14.11 mmol) was added, followed by slowaddition of isopropyl carbonochloridate (3.39 mL, 6.77 mmol) solutionafter cooling in an ice-water bath to ˜10° C. After the addition wascomplete, the reaction mixture was removed from the water bath and themixture was stirred at room temperature for 1 hour. LC/MS showed a smallamount of starting material. Additional isopropyl chloroformate (0.4 mL)solution was added, and the reaction mixture was stirred at roomtemperature for 30 more minutes, at which point complete conversion wasnoted. The reaction mixture was diluted with diethyl ether and stirredwith saturated aqueous sodium bicarbonate for 20 minutes. The layerswere separated and the organic layer was washed twice with 1M aqueousHCl and brine, dried over sodium sulfate, filtered, and concentrated.The crude material was loaded onto a 40 g silica gel cartridge, elutingwith a gradient of 5-100% ethyl acetate/heptanes over a period of 40minutes. The product was precipitated from hexanes to provide(2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-nitropyrrolidine-1,2-dicarboxylate(2.086 g, 4.73 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.63(t, J=1.5 Hz, 1H), 7.48-7.41 (m, 1H), 7.29-7.20 (m, 2H), 5.64 (dd,J=8.7, 3.0 Hz, 1H), 5.44 (d, J=8.7 Hz, 1H), 4.70 (p, J=6.2 Hz, 1H), 4.51(d, J=3.6 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.96 (t, J=3.3 Hz, 1H), 1.30(t, J=7.1 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H), 1.01 (s, 9H), 0.95 (d, J=6.2Hz, 3H); MS (ESI+) m/z 441 (M+H)⁺.

Example 79B (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 79A (1.4 g, 3.18 mmol) was dissolved in ethanol (28.6 mL) andthe solution was heated to 75° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (2.99 g, 7.94 mmol) in 6Maqueous hydrochloric acid (57.2 mL) and adding Zn (5.71 g, 87 mmol) inportions while cooling in an ice bath. The suspension was stirred atroom temperature for 30 minutes after removing from the ice bath,leaving a brilliant blue solution. The CrCl₂ solution was transferredvia cannula over 60 minutes to the solution of starting material andheating was continued for 16 hours. The mixture was cooled to roomtemperature, poured into a separatory funnel, extracted three times withdichloromethane, dried over sodium sulfate, filtered, and concentrated.The crude material was redissolved in ethanol and subjected tore-esterification. Acetyl chloride (3 mL, 42.2 mmol) was added slowly toice-cooled flask containing ethanol (9 mL). After the addition wascomplete, the reaction was stirred at room temperature for 5 minutesbefore pouring the resulting HCl/ethanol solution into a separate flaskcontaining the crude ester/acid mixture. The mixture was heated to 65°C. for an additional hour, at which point nearly complete conversion wasnoted. The mixture was cooled to room temperature, concentrated anddiluted with ether. The mixture was poured into a separatory funnel andwashed three times with 1M aqueous HCl, three times with saturatedaqueous sodium bicarbonate, and once with brine. The combined organicswere dried over sodium sulfate, filtered, and concentrated to providethe crude product. The crude product was purified on a 24 g cartridgeeluting with a gradient of 0-70% ethyl acetate/heptanes over a period of20 minutes to provide the desired product (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxylate(0.28 g, 0.683 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (s, 1H), 7.46(dd, J=7.5, 1.5 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.35-7.30 (m, 1H), 5.09(s, 1H), 4.66 (d, J=13.2 Hz, 1H), 4.55 (d, J=4.3 Hz, 1H), 4.19 (dd,J=10.4, 3.9 Hz, 2H), 2.64 (d, J=4.4 Hz, 1H), 1.23 (t, J=7.1 Hz, 3H),1.13 (m, 3H), 1.02 (s, 9H), 0.72 (s, 3H); MS (APCI+) m/z 410 (M+H)⁺.

Example 79C (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 79B (0.28 g, 0.683 mmol) was dissolved in ethanol (3.42 mL) andsodium borohydride (0.052 g, 1.366 mmol) was added after cooling thereaction to <−60° C. in a dry ice/acetone bath. The ice bath was removedand the mixture was allowed to warm to room temperature over about 20minutes, at which point LC/MS showed the starting material to becompletely consumed. The mixture was concentrated then partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organiclayer was concentrated and purified on a 40 g silica gel cartridge,eluting with 0-70% ethyl acetate/heptanes over 20 minutes. The desiredproduct was precipitated from hexane to provide (2S,3R,4S,5S)-2-ethyl1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate(160 mg, 0.388 mmol, 56.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.66(s, 1H), 7.44 (dt, J=7.6, 1.4 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.22(ddd, J=8.0, 2.2, 1.2 Hz, 1H), 4.79 (t, J=5.5 Hz, 2H), 4.61 (d, J=40.7Hz, 1H), 4.32 (dd, J=6.5, 4.2 Hz, 1H), 4.20 (s, 1H), 4.18-4.10 (m, 2H),2.16 (t, J=4.4 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.11 (m, 3H), 0.96 (s,9H), 0.88-0.59 (m, 3H); MS (APCI+) m/z 396 (M+H)⁺.

Example 79D (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 79C (50 mg, 0.121 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (68.0 mg, 0.252mmol) were dissolved in dry dimethylformamide (0.607 mL). After coolingin an ice bath, potassium 2-methylpropan-2-olate (0.194 mL, 0.194 mmol)solution was added dropwise over 2 minutes. The reaction was stirred for30 minutes, then acidified with 1M aqueous HCl (5 drops) and warmed toroom temperature. The reaction mixture was diluted with water (2 mL) andextracted with dichloromethane. The extracts were loaded onto a 12 gsilica gel cartridge and eluted with 0-60% ethyl acetate/heptanes over20 minutes to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(3-chlorophenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate,2096-1 (61 mg, 0.101 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.37 (s, 1H), 7.71 (s, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.22 (t, J=7.7 Hz,1H), 7.17 (d, J=8.6 Hz, 2H), 5.04 (s, 1H), 4.60 (s, 1H), 4.40-4.28 (m,3H), 4.07 (td, J=10.9, 10.3, 7.1 Hz, 2H), 3.90 (d, J=13.7 Hz, 1H), 3.85(s, 3H), 2.41 (s, 1H), 1.30-1.04 (m, 6H), 0.99 (s, 9H), 0.89-0.59 (m,3H); MS (APCI+) m/z 602 (M+H)⁺.

Example 79E(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a mixture of Example 79D (60 mg, 0.100 mmol) in tetrahydrofuran (300μL), methanol (300 μL) and water (300 μL) was added lithium hydroxidehydrate (29.3 mg, 0.699 mmol) and the reaction heated at 45° C. over theweekend. LC/MS showed the desired product and the solvent was removedunder a stream of nitrogen. The crude material was acidified with 2Maqueous HCl (350 uL), extracted with dichloromethane and purified usinga 4 g silica gel column eluting with a gradient 0-10%methanol/dichloromethane over a period of 15 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-5-(3-chlorophenyl)-1-(isopropoxycarbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylicacid (39 mg, 0.068 mmol, 68.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.67 (bs, 1H), 8.37-8.31 (m, 1H), 7.77 (s, 1H), 7.54 (d, J=7.4 Hz, 1H),7.18 (t, J=7.7 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.06 (s, 1H), 4.99 (d,J=6.0 Hz, 1H), 4.57 (s, 1H), 4.33 (d, J=14.4 Hz, 1H), 4.28 (d, J=6.3 Hz,1H), 4.25 (d, J=2.3 Hz, 1H), 3.91 (d, J=14.4 Hz, 1H), 3.84 (s, 3H), 2.44(s, 1H), 1.18-1.02 (m, 3H), 0.96 (s, 9H), 0.65 (s, 3H); MS (APCI+) m/z574 (M+H)⁺.

Example 80(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(3-chlorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedure described in Example79 substituting 3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine. ¹H NMR (501 MHz,DMSO-d₆) δ ppm 12.62 (bs, 1H), 7.92 (d, J=2.7 Hz, 1H), 7.81 (s, 1H),7.59 (d, J=7.5 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H),7.09 (s, 1H), 4.99 (s, 1H), 4.61 (d, J=43.6 Hz, 1H), 4.26 (d, J=13.5 Hz,3H), 3.88 (d, J=13.6 Hz, 1H), 3.74 (s, 3H), 2.44 (s, 1H), 1.17 (s, 9H),1.11 (m, 3H), 0.97 (s, 9H), 0.66 (s, 3H); MS (APCI+) m/z 562 (M+H)⁺.

Example 81(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(piperidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a 4 mL vial was addeddichloro[4,5-dichloro-1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl, 3.73 mg, 4.33 μmol 0.1 eq) and potassium t-butoxide(12.14 mg, 0.108 mmol (2.5 eq) in dimethoxyethane (DME) (0.5 mL) toprovide a yellow suspension. The vial was placed under nitrogen. Example40A (25 mg, 0.043 mmol, 1.0 eq) and piperidine (6.41 μL, 0.065 mmol, 1.5eq) in dimethoxyethane (0.5 mL) were added. The reaction was stirred at90° C. for 4 hours. The solvent was removed under a stream of nitrogen.The residue was reconstituted in 500 uL 3:2 tetrahydrofuran/methanol.LiOH monohydrate (5 M, 200 μL) was added and the reaction was stirred at45° C. overnight. The solvent was removed under a stream of nitrogen.The mixture was acidified with 2 M aqueous HCl and extracted withdichloromethane (3×1 mL). The solvent was removed under a stream ofnitrogen. The residue was reconstituted in dimethyl sulfoxide/methanoland purified on reverse phase HPLC using method AA6 to provide the titlecompound (7.5 mg, 31% yield). ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 7.66-7.60 (m, 2H), 7.50 (d, J=3.0 Hz, 1H), 7.23-7.06 (m,3H), 6.70 (d, J=3.1 Hz, 1H), 4.95 (d, J=6.5 Hz, 1H), 4.60 (p, J=6.2 Hz,1H), 4.23 (d, J=3.2 Hz, 1H), 4.18 (d, J=13.3 Hz, 1H), 4.13 (dd, J=6.5,2.5 Hz, 1H), 3.85 (d, J=13.2 Hz, 1H), 3.71 (s, 3H), 2.93-2.80 (m, 5H),1.67-1.56 (m, 4H), 1.56-1.45 (m, 2H), 1.04 (d, J=6.3 Hz, 3H), 0.97 (s,9H), 0.87 (d, J=6.1 Hz, 3H); MS (APCI+) m/z 554.1 (M+H)⁺.

Example 82(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 81 substituting pyrrolidine for piperidine. ¹H NMR (400 MHz,120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 7.60-7.53 (m, 2H), 7.28-7.07 (m,4H), 6.52 (s, 1H), 4.96 (d, J=6.2 Hz, 1H), 4.62 (p, J=6.2 Hz, 1H), 4.31(d, J=3.1 Hz, 1H), 4.22-4.12 (m, 2H), 3.84 (d, J=13.1 Hz, 1H), 3.69 (s,3H), 3.06-2.99 (m, 4H), 2.49-2.43 (m, 1H), 1.96-1.87 (m, 4H), 1.04 (d,J=6.2 Hz, 3H), 0.98 (s, 9H), 0.87 (d, J=6.2 Hz, 3H); MS (APCI+) m/z540.1 (M+H)⁺.

Example 83(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 83A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-nitro-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

To a cooled (ice bath) solution of Core 9 (1.86 g, 5.56 mmol) indichloromethane (11.12 mL) was added triethylamine (2.326 mL, 16.69mmol) followed by addition of isopropyl carbonochloridate (3.34 mL, 6.67mmol) as a solution in toluene maintaining an internal temperature<10°C. After the addition was complete, the ice bath was removed and themixture was stirred at room temperature. After 6 hours, additionaltriethylamine (1 mL, 7.17 mmol) was added, followed by 1 mL of 2Misopropyl chloroformate solution. The reaction was stirred at roomtemperature overnight, diluted with methyl tert-butyl ether (200 mL),and stirred with 50 mL of saturated aqueous ammonium chloride at roomtemperature for 15 minutes. The organic layer was separated and washedwith 1N aqueous HCl and brine then dried over sodium sulfate. Afterfiltration, the solvent was removed to provide 2.22 g of startingmaterial and product, which was resubjected to the reaction conditionsand worked up as described. The resulting crude material waschromatographed using an 80 g silica gel cartridge with a gradient of5-50% methyl tert-butyl ether/heptanes to provide (2S,3R,4S,5S)-2-ethyl1-isopropyl3-(tert-butyl)-4-nitro-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate (1.44 g,3.42 mmol, 61.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.78 (dd,J=7.9, 1.8 Hz, 1H), 7.14-7.02 (m, 3H), 5.54 (d, J=2.7 Hz, 2H), 4.64 (p,J=6.2 Hz, 1H), 4.49 (d, J=4.0 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.07 (dd,J=4.1, 2.4 Hz, 1H), 2.36 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.05 (d, J=6.2Hz, 3H), 1.02 (s, 9H), 0.88 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 421(M+H)⁺.

Example 83B (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-oxo-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

Example 83A (0.900 g, 2.140 mmol) was dissolved in ethanol (22 mL) andthe solution was heated to 75° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (2.013 g, 5.35 mmol) inaqueous hydrochloric acid (6M, 44 mL) and adding Zn (3.85 g, 58.9 mmol)in portions while cooling in an ice bath. The suspension was stirred atroom temperature for 30 minutes after removing from the ice bath, andthe suspension stirred for another 30 minutes, leaving a clear brilliantblue solution. The CrCl₂ solution was transferred via cannula over 20minutes to the solution of starting material. The reaction mixture washeated between 75 and 80° C. for 10 hours, allowed to cool to roomtemperature, poured into a separatory funnel, and extracted with 3×200mL of dichloromethane. The extracts were dried over sodium sulfate andfiltered and the solvent was removed in vacuo. The crude material wasre-esterified, dissolving it in 6 mL of ethanol and adding a preparedsolution of 4 mL ethanol and 1 mL of acetyl chloride (combined at 0°C.). The mixture was warmed at 65° C. for an hour, the solvent wasreduced in volume, and the crude material was chromatographed using a 40g silica gel cartridge with a gradient of 5-100% ethyl acetate/heptanesto provide (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-oxo-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate (0.540 g,1.386 mmol, 64.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.67-7.59 (m,1H), 7.13 (dtt, J=14.2, 7.2, 3.9 Hz, 3H), 5.17 (s, 1H), 4.69 (ddd,J=12.4, 6.6, 5.8 Hz, 1H), 4.57 (d, J=5.2 Hz, 1H), 4.23 (qd, J=7.1, 2.1Hz, 2H), 2.61 (d, J=5.2 Hz, 1H), 2.38 (s, 3H), 1.26 (t, J=7.1 Hz, 3H),1.08 (d, J=6.2 Hz, 3H), 1.06 (s, 9H), 0.90 (d, J=6.1 Hz, 3H); MS (APCI+)m/z 389 (M+H)⁺.

Example 83C (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

Example 83B (0.54 g, 1.386 mmol) was dissolved in ethanol (6.93 mL) andsodium borohydride (0.105 g, 2.77 mmol) was added after cooling thereaction to <−10° C. in a dry ice/acetone bath. The ice bath was removedand the mixture was allowed the reaction to warm to room temperature.The reaction mixture was concentrated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organics wereconcentrated and purified on a 24 g silica gel cartridge, eluting with0-70% ethyl acetate/heptanes over 20 minutes provide(2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate,2101-T (0.348 g, 0.889 mmol, 64.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 7.94-7.78 (m, 1H), 7.15-6.96 (m, 3H), 4.96 (d, J=6.7 Hz, 1H), 4.58(d, J=5.1 Hz, 1H), 4.54 (bs, 1H), 4.40-4.32 (m, 1H), 4.17 (d, J=5.1 Hz,1H), 4.14 (q, J=7.1, 2H), 2.27 (s, 3H), 2.22 (t, J=4.8 Hz, 1H), 1.23 (t,J=7.1 Hz, 3H), 1.05 (bs, 3H), 0.95 (s, 9H), 0.57 (s, 3H); MS (APCI+) m/z392 (M+H)⁺.

Example 83D 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

To a solution of (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate,Example 83C (70 mg, 0.179 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (100 mg, 0.371mmol) were dissolved in dry dimethylformamide (0.894 mL). After coolingin an ice bath, potassium 2-methylpropan-2-olate (0.194 mL, 0.194 mmol)solution was added dropwise over 2 minutes. After 30 minutes, themixture was acidified with 1M aqueous HCl (5 drops) and the mixture waswarmed to room temperature. The mixture was diluted with water (2 mL)and extracted with dichloromethane. The extracts were loaded onto a 12 gsilica gel cartridge and were eluted with 0-60% ethyl acetate/heptanesover 20 minutes to provide (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate(59 mg, 0.102 mmol, 56.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.34(d, J=2.4 Hz, 1H), 7.88 (s, 1H), 7.02 (d, J=3.5 Hz, 4H), 5.10 (d, J=5.5Hz, 1H), 4.57 (s, 2H), 4.46-4.24 (m, 3H), 4.18-3.99 (m, 2H), 3.84 (m,4H), 2.31 (s, 3H), 1.25-1.13 (m, 3H), 1.10 (t, J=7.1 Hz, 3H), 1.01 (s,9H), 0.87-0.48 (m, 3H); MS (APCI+) m/z 582 (M+H)⁺.

Example 83E(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a solution of Example 83D (58 mg, 0.100 mmol) in tetrahydrofuran (300μL), methanol (300 μL) and water (300 μL) was added lithium hydroxide(29.3 mg, 0.699 mmol) and the reaction was heated at 45° C. for 72hours. The solvent was removed under a stream of nitrogen. The crudematerial was acidified with 2M aqueous HCl (350 uL) to pH˜5, extractedwith dichloromethane, and purified using a 4 g silica gel column. Thecolumn was eluted with a gradient of 0-10% methanol/dichloromethane overa period of 20 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-1-(isopropoxycarbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-2-carboxylicacid (28 mg, 0.051 mmol, 50.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.60 (s, 1H), 8.38-8.22 (m, 1H), 7.94 (s, 1H), 7.00 (m, 4H), 5.06 (d,J=5.7 Hz, 1H), 4.54 (m, 2H), 4.32 (d, J=3.2 Hz, 2H), 4.30 (d, J=5.7 Hz,1H), 3.87 (d, J=14.5 Hz, 1H), 3.83 (s, 3H), 2.27 (s, 3H), 1.21-1.02 (m,3H), 0.99 (s, 9H), 0.82-0.5 (m, 3H); MS (APCI+) m/z 553 (M+H)⁺.

Example 84(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoroazetidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a 4 mL vial was addeddichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(1.1 mg, 0.0013 mmol 0.05 eq) and potassium t-butoxide (8.74 mg, 0.078mmol, 3.0 eq) in dimethoxyethane (DME, 0.5 mL) to provide a yellowsuspension. The vial was placed under nitrogen. 3,3-Difluoroazetidinehydrochloride (5.05 mg, 0.039 mmol, 1.5 eq) was added. The mixture wasstirred at 85° C. for 30 minutes. Example 40A (15 mg, 0.026 mmol, 1.0eq) was added. The reaction was stirred at 85° C. for 4 hours. Thesolvent was removed under a stream of nitrogen. The residue wasreconstituted in 500 uL 3:2 tetrahydrofuran:methanol. LiOH monohydrate(5 M, 200 μL) was added and the reaction was stirred at 45° C.overnight. The solvent was removed under a stream of nitrogen. Thereaction was acidified with 2 M aqueous HCl and was extracted withdichloromethane (3×1 mL). The solvent was removed under a stream ofnitrogen. The residue was reconstituted in DMSO/methanol and purified onreverse phase HPLC using method AA6 to provide the title compound (4.0mg, 27% yield). ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm7.64-7.53 (m, 2H), 7.26 (d, J=3.0 Hz, 1H), 7.23-7.00 (m, 3H), 6.46-6.40(m, 1H), 4.95 (d, J=6.2 Hz, 1H), 4.62 (hept, J=6.1 Hz, 1H), 4.31 (d,J=2.9 Hz, 1H), 4.22-4.03 (m, 6H), 3.82 (d, J=13.3 Hz, 1H), 3.71 (s, 3H),2.45 (t, J=2.6 Hz, 1H), 1.04 (d, J=6.1 Hz, 3H), 0.98 (s, 9H), 0.87 (d,J=6.2 Hz, 3H); MS (APCI+) m/z 561.9 (M+H)⁺.

Example 85(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoropyrrolidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 84 substituting 3,3-difluoropyrrolidine hydrochloride for3,3-difluoroazetidine hydrochloride and using 4.0 eq of potassiumt-butoxide instead of 3.0 eq. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 7.56 (d, J=7.4 Hz, 2H), 7.31 (d, J=3.0 Hz, 1H), 7.14 (dt,J=28.0, 7.4 Hz, 3H), 6.51 (d, J=3.1 Hz, 1H), 4.96 (d, J=6.2 Hz, 1H),4.62 (p, J=6.2 Hz, 1H), 4.32 (d, J=2.9 Hz, 1H), 4.24-4.13 (m, 2H), 3.85(d, J=13.3 Hz, 1H), 3.70 (s, 3H), 3.45 (td, J=13.2, 3.8 Hz, 2H), 3.30(td, J=7.2, 4.3 Hz, 2H), 2.47-2.37 (m, 3H), 1.04 (d, J=6.2 Hz, 3H), 0.99(s, 9H), 0.87 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 576.2 (M+H)⁺.

Example 86(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 86A (2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-1,2-dicarboxylate

To a solution of Core 10 (1.487 g, 3.72 mmol) in pyridine (10 mL) wasadded isopropyl carbonochloridate (6 mL, 6.00 mmol) as a solution intoluene. The reaction was stirred at room temperature for 18 hours.Additional carbamoyl chloride (4 mL, 4 mmol) was added and the mixturewas stirred for 1 hour more. The mixture was diluted with methyltert-butyl ether and filtered through diatomaceous earth. The solventwas removed in vacuo. The crude material was diluted withdichloromethane (200 mL), washed with 50 mL of 1M aqueous HCl, andconcentrated. The bright yellow residue was purified on an 80 g silicagel cartridge with a gradient of 5-50% ethyl acetate in heptanes toprovide (2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-1,2-dicarboxylate(1.486 g, 3.06 mmol, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.87(dd, J=7.9, 1.7 Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.30 (td, J=7.6,1.2 Hz, 1H), 7.18 (td, J=7.7, 1.7 Hz, 1H), 5.66 (d, J=8.5 Hz, 1H), 5.50(dd, J=8.5, 2.7 Hz, 1H), 4.72-4.63 (m, 1H), 4.55 (d, J=3.4 Hz, 1H), 4.27(qd, J=7.1, 0.8 Hz, 2H), 3.04 (t, J=3.1 Hz, 1H), 1.30 (td, J=7.0, 0.8Hz, 3H), 1.07 (d, J=6.2 Hz, 3H), 1.03 (d, J=0.9 Hz, 9H), 0.91 (d, J=6.2Hz, 3H); MS (APCI+) m/z 485 (M+H)⁺.

Example 86B (2S,3R,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 86A (1.48 g, 3.05 mmol) was dissolved in ethanol (35 mL) and thesolution was heated to 75° C. A separate solution of CrCl₂ was preparedby dissolving pyridinium dichromate (2.87 g, 7.62 mmol) in aqueoushydrochloric acid (6M, 70 mL) and adding Zn (5.48 g, 84 mmol) inportions while cooling in an ice bath. The suspension was stirred atroom temperature for 30 minutes after removing from the ice bath, andthe suspension was stirred for another 30 minutes, leaving a clearbrilliant blue solution. The CrCl₂ solution was transferred via cannulaover 20 minutes to the solution of starting material (internal temp 79°C.). The reaction mixture was stirred at this temperature for 23 hours,heating was continued for 7 more hours at 91° C., and the mixture wascooled to room temperature. The mixture was poured into a separatoryfunnel and extracted with 3×150 mL of dichloromethane. The extracts weredried over sodium sulfate, filtered, and the solvent was removed invacuo. The crude material was re-esterified by dissolving in 6 mL ofethanol and adding a prepared solution of 4 mL ethanol and 1.5 mL ofacetyl chloride (combined at 0° C.), and then warming at 65° C. for anhour. The solvent was removed and the crude material was taken up in 100mL of ethyl acetate and washed with saturated aqueous sodiumbicarbonate. The organics were dried over sodium sulfate and filtered.The solvent was removed in vacuo to provide (2S,3R,5S)-2-ethyl1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-oxopyrrolidine-1,2-dicarboxylate(1.38 g, 2.430 mmol, 80% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.80(dd, J=7.8, 1.8 Hz, 1H), 7.59 (dd, J=8.0, 1.3 Hz, 1H), 7.32 (td, J=7.5,1.4 Hz, 1H), 7.20 (dd, J=7.6, 1.8 Hz, 1H), 5.41 (s, 1H), 4.74-4.66 (m,1H), 4.58 (dd, J=4.6, 0.6 Hz, 1H), 4.27-4.22 (m, 2H), 2.61 (dd, J=4.6,0.9 Hz, 1H), 1.26 (t, J=7.0 Hz, 3H), 1.09 (d, J=6.3 Hz, 3H), 1.06 (s,9H), 0.89 (d, J=6.1 Hz, 3H); MS (APCI+) m/z 455 (M+H)⁺.

Example 86C (2S,3R,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 86B (1.38 g, 3.04 mmol) was dissolved in ethanol (20 mL) and themixture was cooled in an acetone/ice bath to ˜−9° C. Sodiumtetrahydroborate (0.138 g, 3.64 mmol) was added, initially in smallportions but then all at once. The mixture was allowed to stir in thebath for 30 minutes, and concentrated in vacuo. Ethyl acetate (200 mL)and saturated aqueous sodium bicarbonate (50 mL) were added and themixture was stirred for 30 minutes at room temperature. The organiclayer was washed with brine, dried over sodium sulfate, filtered, andconcentrated. The crude material was loaded onto a 40 g silica gelcolumn and was eluted with 0-100% methyl tert-butyl ether/heptanes toprovide (2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylateand (2S,3R,4R,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylateas a 2:1 mixture (0.650 g, 1.424 mmol, 46.9% yield). This mixture wascarried forward for subsequent reactions ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.93 (dd, J=7.8, 1.8 Hz, 1H), 7.47 (dd, J=8.0, 1.2 Hz, 1H), 7.25 (td,J=7.6, 1.2 Hz, 1H), 7.09 (td, J=7.6, 1.8 Hz, 1H), 5.17 (d, J=6.0 Hz,1H), 4.62 (p, J=6.2 Hz, 1H), 4.44 (td, J=5.5, 2.3 Hz, 1H), 4.32 (d,J=3.2 Hz, 1H), 4.23-4.14 (m, 3H), 2.28 (t, J=2.8 Hz, 1H), 1.25 (t, J=7.1Hz, 3H), 1.04 (d, J=6.1 Hz, 3H), 0.99 (s, 9H), 0.87 (d, J=6.2 Hz, 3H);MS (APCI+) m/z 457 (M+H)⁺ Br doublet.

Example 86D (2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

3-(Bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (0.433 g, 1.603mmol) and Example 86C (0.500 g, 1.096 mmol) were dissolved indimethylformamide (3.0 mL) cooled in an ice bath, and KOtBu (potassiumtert-butoxide) (1.5 mL, 1.500 mmol) was added dropwise. After 30minutes, the mixture was diluted with 100 mL of methyl tert-butyl etherand quenched with 15 mL of saturated aqueous ammonium chloride. Theorganic layer was washed with 20 mL of water and brine, dried oversodium sulfate, filtered, and concentrated. The crude material waspurified using a 40 g silica gel cartridge with a gradient of 5-50%methyl tert-butyl ether/heptanes over 40 minutes to provide desired(2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate(0.304 g, 0.471 mmol, 43.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.33-8.26 (m, 1H), 7.96 (dd, J=7.8, 1.8 Hz, 1H), 7.44 (dd, J=8.0, 1.3Hz, 1H), 7.21 (td, J=7.6, 1.3 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.07 (td,J=7.6, 1.8 Hz, 1H), 5.29 (d, J=5.7 Hz, 1H), 4.66 (p, J=6.2 Hz, 1H), 4.47(d, J=2.1 Hz, 1H), 4.37 (dd, J=5.7, 1.2 Hz, 1H), 4.32 (dt, J=13.6, 0.9Hz, 1H), 4.11 (qd, J=7.1, 2.3 Hz, 2H), 3.98-3.92 (m, 1H), 3.87 (s, 3H),2.52-2.48 (m, 1H), 1.15 (t, J=7.1 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.03(s, 9H), 0.90 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 645 (M+H).

Example 86E(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 86D (58 mg, 0.090 mmol) and lithium hydroxide (20.4 mg, 0.852mmol) were dissolved in methanol (0.5 mL), tetrahydrofuran (0.500 mL)and water (0.500 mL). The reaction was warmed at 45° C. overnight. Thesolvent was removed under a stream of nitrogen and the mixture wasacidified with of 2N aqueous HCl (0.422 mL). The mixture waschromatographed using a 12 g silica gel cartridge with an ethanol/ethylacetate/heptanes solvent system to provide(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-1-(isopropoxycarbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylicacid (43 mg, 0.070 mmol, 78% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.29 (d, J=2.5 Hz, 1H), 8.08 (dd, J=7.8, 1.8 Hz, 1H), 7.42 (dd, J=7.9,1.3 Hz, 1H), 7.19 (td, J=7.6, 1.3 Hz, 1H), 7.15 (s, 1H), 7.05 (td,J=7.6, 1.8 Hz, 1H), 5.28 (d, J=5.9 Hz, 1H), 4.65 (p, J=6.2 Hz, 1H), 4.40(d, J=2.1 Hz, 1H), 4.38-4.29 (m, 2H), 4.01-3.94 (m, 1H), 3.87 (s, 3H),2.53 (d, J=1.7 Hz, 1H), 1.06 (d, J=6.2 Hz, 3H), 1.02 (s, 9H), 0.89 (d,J=6.2 Hz, 3H); MS (APCI+) m/z 617 (M+H)⁺.

Example 87(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 87A 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

Core 13 (500 mg, 1.38 mmol) was dissolved in dichloromethane (4 mL) andtrimethylamine (1.54 mL, 11.0 mmol) was added, followed by isopropylchloroformate (1M in toluene, 4.14 mL, 8.28 mmol). The reaction wasstirred at ambient temperature for 4 hours, at which point it wascomplete. The reaction was diluted with dichloromethane (50 mL) andwashed with 1M aqueous HCl (2×50 mL) and brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated to provide thecrude product. The residue was purify by silica gel chromatography (0%to 20% ethyl acetate in heptanes) to provide the title compound (363 mg,59%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.88-7.81 (m, 1H),7.24-7.11 (m, 2H), 7.04 (ddd, J=8.4, 6.5, 2.1 Hz, 1H), 5.65 (d, J=8.9Hz, 1H), 5.51 (dd, J=8.9, 3.5 Hz, 1H), 4.65 (m, 1H), 4.49 (d, J=4.2 Hz,1H), 4.26 (q, J=7.1 Hz, 2H), 3.22 (h, J=6.8 Hz, 1H), 3.06 (m, 1H),1.34-1.17 (m, 9H), 1.03 (d, J=6.2 Hz, 3H), 1.02 (s, 9H), 0.84 (d, J=6.4Hz, 3H).; MS (ESI+) m/z 449 (M+H)⁺.

Example 87B 2-ethyl 1-isopropyl(2S,3R,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 87A (363 mg, 0.809 mmol) was dissolved in 9 mL of ethanol andthe solution was heated to 75° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (761 mg, 2.02 mmol) in 18mL of 6M aqueous HCl and adding Zn (1.455 g, 22.25 mmol) in portionswhile cooling in an ice bath. The suspension was stirred until all theZn dissolved, leaving a brilliant blue solution. The CrCl₂ solution wastransferred via cannula over 15 minutes to the solution of startingmaterial and heating was continued for 16 hours. The temperature wasmaintained between 70° C. and 75° C. during the addition. The reactionmixture was continuously heated between 75° C. and 80° C. overnight,cooled to room temperature, diluted with water and extracted withdichloromethane (3×30 mL). The combined extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. The crude residuewas dissolved in ethanol (5 mL). A separate solution of HCl/ethanol wasprepared by addition of 0.5 mL of acetyl chloride to 1.5 mL of ethanolat 0° C., and it was poured into the reaction flask and heated to 45° C.for 1 hour. The reaction mixture was concentrated in vacuo and loadedonto a 40 g silica gel cartridge, eluting with 5-100% ethylacetate/heptanes over to provide the title compound (156 mg, 46%). ¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.68 (dd, J=7.8, 1.4 Hz, 1H), 7.29(dd, J=7.8, 1.5 Hz, 1H), 7.20 (td, J=7.5, 1.5 Hz, 1H), 7.09 (td, J=7.5,1.5 Hz, 1H), 5.28 (m, 1H), 4.69 (p, J=6.2 Hz, 1H), 4.57 (d, J=5.5 Hz,1H), 4.23 (m, 2H), 3.32 (p, J=6.8 Hz, 1H), 2.62 (dd, J=5.5, 0.9 Hz, 1H),1.30-1.23 (m, 6H), 1.21 (d, J=6.8 Hz, 3H), 1.06 (m, 12H), 0.87 (d, J=6.2Hz, 3H); MS (ESI+) m/z 418 (M+H)⁺.

Example 87C (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-(2-isopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 87B (156 mg, 0.374 mmol) was dissolved in ethanol (5 mL), andthe reaction mixture was cooled to 0° C. Sodium borohydride (25.9 mg,0.685 mmol) was added and the reaction was stirred at 0° C. for 1 hour,and warmed to ambient temperature for another hour. The solvent wasremoved in vacuo and the residue was extracted with ethyl acetate (50mL), washed with saturated aqueous NaHCO₃ (50 mL) and brine (50 mL),dried over Na₂SO₄, filtered, and concentrated to provide crude product.The crude material was purified by silica gel chromatography (0 to 5%ethyl acetate in dichloromethane) to provide the title compound (107.5mg, 69%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.90 (dd, J=7.8, 1.4Hz, 1H), 7.20 (dd, J=7.8, 1.4 Hz, 1H), 7.13 (td, J=7.4, 1.4 Hz, 1H),7.05 (td, J=7.5, 1.4 Hz, 1H), 5.17 (d, J=6.6 Hz, 1H), 4.60 (pd, J=6.2,0.9 Hz, 1H), 4.33 (dd, J=6.6, 3.8 Hz, 1H), 4.25 (d, J=4.5 Hz, 1H), 4.18(qd, J=7.1, 0.9 Hz, 2H), 3.19 (hept, J=6.8 Hz, 1H), 2.26 (t, J=4.2 Hz,1H), 1.29-1.20 (m, 9H), 1.02-0.98 (m, 12H), 0.82 (d, J=6.2 Hz, 3H); MS(ESI+) m/z 420 (M+H)⁺.

Example 87D 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 87C (48.0 mg, 0.114 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (57.7 mg, 0.214mmol) were dissolved in dimethylformamide (1 mL). The reaction wascooled to 0° C., then potassium tert-butoxide (1M in tetrahydrofuran,0.18 mL, 0.18 mmol) was added dropwise and the reaction was stirred atambient temperature for 1 hour. The reaction was quenched by theaddition of 1M aqueous HCl (0.1 mL) and was purified by silica gelchromatography (0 to 5% ethyl acetate in dichloromethane) to provide thetitle compound (107.5 mg, 69%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm8.27 (s, 1H), 7.92 (dd, J=7.9, 1.4 Hz, 1H), 7.23-6.92 (m, 4H), 5.26 (d,J=5.6 Hz, 1H), 4.70-4.57 (m, J=6.2 Hz, 1H), 4.44 (d, J=2.1 Hz, 1H),4.29-4.19 (m, 2H), 4.17-4.08 (m, 2H), 3.85 (s, 3H), 3.78 (d, J=13.8 Hz,1H), 3.21 (dq, J=12.9, 6.6 Hz, 1H), 1.24 (d, J=6.8 Hz, 3H), 1.21-1.15(m, 6H), 1.04 (s, 9H), 1.00 (d, J=8.1 Hz, 3H), 0.83 (d, J=6.2 Hz, 4H);MS (ESI+) m/z 609 (M+H)⁺.

Example 87E(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 87D (42.8 mg, 0.070 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). LiOH (1 M, 0.5 mL, 0.5 mmol) was added and thereaction was heated to 50° C. for 16 hours. The reaction was quenched bythe addition of 1M aqueous HCl (0.5 mL) and was purified by silica gelchromatography (5 to 100% ethyl acetate in dichloromethane) to providethe title compound (21.8 mg, 53%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δppm 8.26 (s, 1H), 7.24-7.11 (m, 2H), 7.12-7.03 (m, 1H), 6.97 (t, J=7.5Hz, 1H), 5.29-5.20 (m, 1H), 4.69-4.58 (m, 1H), 4.39 (d, J=2.1 Hz, 1H),4.32-4.23 (m, 1H), 4.21 (t, J=5.5 Hz, 1H), 3.89-3.73 (m, 5H), 3.27-3.16(m, 1H), 2.52 (t, J=1.3 Hz, 1H), 1.24 (d, J=6.7 Hz, 3H), 1.17 (d, J=7.0Hz, 3H), 1.06-0.98 (m, 12H), 0.82 (dd, J=6.3, 3.8 Hz, 3H).); MS (ESI+)m/z 581 (M+H)⁺.

Example 88(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid Example 88A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-1,2-dicarboxylate

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-2-carboxylate (1.0 g, 3.12mmol) (Core 5) in toluene (3 mL) and saturated NaHCO₃ (3.00 mL) wasadded allyl carbonochloridate (0.332 mL, 3.12 mmol) drop wise at ambienttemperature, and the mixture was stirred for 30 minutes. LC/MS indicatedthe conversion was finished. Dichloromethane (20 mL) and water (10 mL)were added and the organic layer washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified via silica gelchromatography, eluting with ethyl acetate in heptane at 0-40% gradientto provide the title compound (1.0 g, 95% yield). ¹H NMR (501 MHz,CDCl₃) δ ppm 7.58-7.51 (m, 2H), 7.37-7.26 (m, 3H), 5.61 (s, 2H), 5.43(d, J=8.7 Hz, 1H), 5.30 (dd, J=8.7, 2.6 Hz, 1H), 5.00 (s, 1H), 4.70 (s,1H), 4.56 (s, 2H), 4.39 (qd, J=7.1, 1.8 Hz, 2H), 3.11 (t, J=2.9 Hz, 1H),1.40 (t, J=7.1 Hz, 3H), 1.10 (s, 9H); MS (ESI+) m/z 405 (M+H)⁺.

Example 88B (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-oxo-5-phenylpyrrolidine-1,2-dicarboxylate

Example 88B was prepared according to the procedure described in Example2B, substituting Example 88A for Example 2A. LC/MS (ESI+)=374.45 (M+H)⁺.

Example 88C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate andExample 88D (2S,3R,4R,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate

To Example 88B (560 mg, 1.5 mmol) in ethanol (4 mL) cooling in anice-bath was added sodium borohydride (113 mg, 3.00 mmol) portionwise.The mixture was stirred in the ice-bath for 30 minutes, and allowed towarm to ambient temperature. LC/MS showed two product peaks, the ratiowas about 6 to 1. The solvent was removed, dichloromethane (20 mL) wasadded and the organics were washed with brine. The organics were driedover MgSO₄, filtered, and concentrated. Purification via chromatography,eluting with ethyl acetate/methanol (9:1) in heptanes at 0-40% gradientprovided title compound as the second eluent (340 mg, 60.4% yield). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.64-7.56 (m, 2H), 7.43-7.36 (m, 2H),7.33-7.28 (m, 1H), 5.55 (s, 1H), 5.04 (s, 1H), 4.97-4.70 (m, 1H),4.64-4.38 (m, 3H), 4.35-4.31 (m, 1H), 4.27 (ddd, J=10.8, 7.0, 3.4 Hz,2H), 2.41-2.32 (m, 1H), 1.47 (d, J=5.0 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H),1.07 (s, 9H); LC/MS (ESI+) m/z 376.5 (M+H)⁺. Also obtained was the otherdiastereomer (2S,3R,4R,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate as thefirst eluent (56 mg, 9.95% yield).

Example 88E (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

To Example 88C (340 mg, 0.906 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (293 mg, 1.087mmol) in dimethylformamide (2 mL) in an ice-bath was added potassium2-methylpropan-2-olate (152 mg, 1.358 mmol, 1.6 mL, 1.0 M intetrahydrofuran) dropwise. The mixture was stirred in ice-bath for 20minutes, and allowed to warm to room temperature. Saturated aqueousNH₄Cl (2 mL) was added, and dichloromethane (20 mL) was added. Themixture was washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification of the residue via chromatography, elutingwith ethyl acetate/methanol (9:1) in heptanes at 0-40% gradient providedthe title compound (380 mg, 71% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.29 (t, J=1.5 Hz, 1H), 7.62-7.52 (m, 2H), 7.26-7.15 (m, 3H), 7.13-7.05(m, 1H), 5.73-5.66 (m, 1H), 5.08 (d, J=6.1 Hz, 1H), 5.04 (dq, J=3.2, 1.8Hz, 1H), 5.01 (t, J=1.7 Hz, 1H), 4.41 (ddd, J=5.1, 3.6, 2.3 Hz, 3H),4.30-4.25 (m, 2H), 4.10 (qd, J=7.1, 2.3 Hz, 2H), 3.87 (s, 3H), 1.15 (t,J=7.0 Hz, 3H), 1.01 (s, 9H); MS (ESI+) m/z 565 (M+H)⁺.

Example 88F (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenylpyrrolidine-2-carboxylate

To Example 88E (320 mg, 0.567 mmol) in a mixture of acetonitrile andwater (3.3 mL, 10:1) was added diethylamine (0.117 mL, 1.134 mmol) andtetrakis(triphenylphosphine) palladium(0) (14.41 mg, 0.012 mmol). Themixture was stirred at ambient temperature overnight. Dichloromethane(10 mL) and water (10 mL) were added. The organic layer was washed withbrine, dried over magnesium sulfate, filtered, and concentrated.Purification via chromatography, eluting with ethyl acetate/methanol(10:1) in heptanes at 0-50% gradient provided the title compound (260mg, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24 (dt, J=1.9, 0.9 Hz,1H), 7.46-7.41 (m, 2H), 7.37 (d, J=2.4 Hz, 1H), 7.35-7.29 (m, 2H),7.28-7.23 (m, 1H), 4.33 (dt, J=14.0, 0.9 Hz, 1H), 4.25 (qd, J=7.2, 0.8Hz, 2H), 4.17 (d, J=4.1 Hz, 1H), 3.94 (dd, J=4.2, 1.4 Hz, 1H), 3.93-3.88(m, 4H), 3.74 (d, J=6.2 Hz, 1H), 2.85 (s, 1H), 2.43 (dd, J=6.3, 1.3 Hz,1H), 1.30 (t, J=7.1 Hz, 3H), 1.06 (s, 9H); MS (ESI+) m/z 563 (M+H)⁺.

Example 88G (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenyl-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

To (S)-tetrahydrofuran-2-carboxylic acid (CAS#87392-07-2) (24.16 mg,0.208 mmol) and a drop of dimethylformamide in dichloromethane (5 mL)was added oxalyl dichloride (52.8 mg, 0.416 mmol) (0.21 mL, 2M indichloromethane). The mixture was stirred for 30 minutes. The solventwas removed under pressure and fresh dichloromethane was added and thesolvent was removed again. The residue was dissolved in dichloromethane(1 mL) and added dropwise to the solution of Example 88F (50 mg, 0.104mmol) and triethylamine (0.139 mL, 0.999 mmol) in dichloromethane (2 mL)in an ice-bath. The mixture was stirred and was allowed to warm toambient temperature. Saturated aqueous NH₄Cl (1 mL) and dichloromethane(10 mL) were added. The organic layer was washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified viachromatography, eluting with ethyl acetate in heptanes at 0-40% gradientto provide title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.22 (dd,J=2.8, 1.3 Hz, 1H), 7.71-7.63 (m, 2H), 7.37-7.22 (m, 4H), 7.07 (d, J=2.3Hz, 1H), 5.46 (d, J=6.1 Hz, 1H), 4.78 (d, J=3.3 Hz, 1H), 4.35 (d, J=13.9Hz, 1H), 4.27-4.13 (m, 4H), 3.94-3.85 (m, 4H), 3.89-3.78 (m, 2H), 3.74(td, J=7.7, 5.6 Hz, 1H), 2.58 (t, J=2.9 Hz, 1H), 2.12-2.01 (m, 1H),1.98-1.86 (m, 1H), 1.72-1.61 (m, 1H), 1.43-1.31 (m, 1H), 1.26 (t, J=7.1Hz, 3H), 1.10 (d, J=9.1 Hz, 1H), 1.08 (s, 9H); MS (ESI+) m/z 579 (M+H)⁺.

Example 88H(2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenyl-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylicacid

Example 88G was dissolved in methanol (1.5 mL) and 6M aqueous LiOH (0.5mL) and stirred at 45° C. overnight. The reaction mixture was adjustedpH to 1˜2 by adding 2M aqueous HCl. The reaction mixture wasconcentrated, taken up in dichloromethane and filtered through a syringefilter. The filtrate was purified via chromatography on a 4 g silica gelcartridge, eluting with methanol in dichloromethane at a 0-20% gradientyield the title compound 30 mg (52.4% yield in two steps). ¹H NMR (400MHz, CDCl₃) δ ppm 8.22 (dd, J=2.6, 1.3 Hz, 1H), 7.72-7.63 (m, 2H),7.36-7.24 (m, 3H), 7.07 (d, J=2.3 Hz, 1H), 5.46 (d, J=6.1 Hz, 1H), 4.78(d, J=3.3 Hz, 1H), 4.35 (d, J=13.9 Hz, 1H), 4.24-4.14 (m, 3H), 3.91 (s,3H), 3.88-3.79 (m, 2H), 3.74 (td, J=7.7, 5.7 Hz, 1H), 2.58 (t, J=2.9 Hz,1H), 2.07 (dddd, J=12.5, 8.6, 6.3, 4.8 Hz, 1H), 1.98-1.82 (m, 1H), 1.66(ddq, J=11.9, 8.9, 7.0 Hz, 1H), 1.37 (dddd, J=12.4, 8.8, 7.8, 6.0 Hz,1H), 1.26 (t, J=7.1 Hz, 3H), 1.08 (s, 9H); MS (ESI+) m/z 551 (M+H)⁺.

Example 89(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid Example 89A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenyl-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylateand Example 89B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenyl-1-((R)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To tetrahydro-2H-pyran-2-carboxylic acid (65.0 mg, 0.499 mmol) indichloromethane (6 mL) and a drop of dimethylformamide was added oxalyldichloride (127 mg, 1.0 mmol, 0.5 mL, 2M in dichloromethane). Themixture was stirred for 30 minutes and the solvent was removed underpressure and fresh dichloromethane was added and removed again. Theresidue was dissolved in dichloromethane (1 mL) and was added dropwiseto the solution of Example 88F (120 mg, 0.250 mmol) and triethylamine(0.139 mL, 1.0 mmol) in dichloromethane (6 mL) cooled with an ice-bath.The mixture was stirred in an ice-bath for 30 minutes and was warmed toroom temperature. LC/MS indicated the reaction was finished and showedtwo diastereoisomers peaks at the ratio about 1:1. Saturated aqueousNH₄Cl (2 mL) and dichloromethane (10 mL) were added. The organic layerwas washed with brine, dried over MgSO₄, filtered, and concentrated.Purification via chromatography on a 24 g silica gel cartridge, elutingwith ethyl acetate in heptanes at 0-40% gradient provided Example 89A asthe first eluent (55 mg, 37.2% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm8.29-8.16 (m, 1H), 7.75-7.61 (m, 2H), 7.40-7.24 (m, 3H), 7.12 (d, J=2.3Hz, 1H), 5.52 (d, J=6.1 Hz, 1H), 4.74 (d, J=3.1 Hz, 1H), 4.32 (d, J=14.1Hz, 1H), 4.21 (qq, J=7.1, 3.7 Hz, 2H), 4.15-4.06 (m, 1H), 3.91 (s, 3H),3.85 (dd, J=13.7, 4.5 Hz, 2H), 3.38 (dd, J=10.3, 2.7 Hz, 1H), 2.95 (td,J=11.5, 2.5 Hz, 1H), 2.51 (t, J=2.7 Hz, 1H), 1.77-1.29 (m, 6H), 1.26 (t,J=7.1 Hz, 3H), 1.07 (s, 9H); MS (ESI+) m/z 593.1 (M+H)⁺. Example 89B wasobtained as the second eluent (52 mg, 35.1% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.22 (tt, J=2.5, 1.2 Hz, 1H), 7.72-7.61 (m, 1H), 7.52-7.48(m, 1H), 7.36-7.31 (m, 1H), 7.30-7.23 (m, 2H), 7.19-7.13 (m, 1H), 5.24(d, J=5.6 Hz, 1H), 5.19 (d, J=1.5 Hz, 1H), 4.34 (dd, J=24.7, 14.0 Hz,1H), 4.28-4.12 (m, 3H), 4.11-3.94 (m, 3H), 3.91 (d, J=7.2 Hz, 3H),3.83-3.73 (m, 1H), 3.47 (td, J=11.1, 2.6 Hz, 1H), 2.70 (s, 1H),1.99-1.60 (m, 4H), 1.56-1.48 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.08 (d,J=13.1 Hz, 9H); MS (ESI+) m/z 593.2 (M+H)⁺.

Example 89C(2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-phenyl-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid

The mixture of Example 89A (50 mg, 0.084 mmol) in methanol (1.5 mL) and6M aqueous LiOH (0.5 mL) was stirred at 45° C. for overnight. Themixture was adjusted to pH to 1˜2 by adding 2M aqueous HCl. The reactionmixture was concentrated, taken up in dichloromethane, and filteredthrough a syringe filter. The filtrate was purified via chromatographyon a 4 g silica gel cartridge, eluting with methanol in dichloromethaneat 0-20% gradient to provide the title compound (30 mg, 63.0% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.37-8.29 (m, 1H), 7.66 (d, J=7.4 Hz, 2H),7.21 (d, J=7.5 Hz, 3H), 7.16 (d, J=7.5 Hz, 1H), 5.42 (s, 1H), 4.55 (s,1H), 4.33-4.25 (m, 2H), 3.91 (d, J=13.9 Hz, 1H), 3.88 (s, 3H), 3.79 (d,J=11.3 Hz, 1H), 3.51 (s, 1H), 2.84 (s, 2H), 1.72-1.26 (m, 6H), 1.00 (s,9H); MS (ESI+) m/z 565.1 (M+H)⁺.

Example 90(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(prop-2-en-1-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

A mixture of Example 88E (45 mg, 0.080 mmol) and lithium hydroxide(19.09 mg, 0.797 mmol) in methanol/water (2 mL, 4:1) was stirred at 50°C. overnight, and LC/MS indicated conversion was complete. The mixturewas adjusted pH to 1˜2 by adding 2M aqueous HCl. The reaction mixturewas concentrated, taken up in dichloromethane, and filtered through asyringe filter. The filtrate was purified via chromatography on a 4 gsilica gel cartridge, eluting with methanol in dichloromethane at 0-20%gradient to provide the title compound (38 mg, 89% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.28 (d, J=2.2 Hz, 1H), 7.64-7.52 (m, 2H), 7.23-7.12(m, 3H), 7.13-7.05 (m, 1H), 5.06 (d, J=6.1 Hz, 1H), 5.04-4.99 (m, 1H),4.40 (dt, J=5.0, 1.7 Hz, 2H), 4.37 (d, J=3.0 Hz, 1H), 4.32-4.24 (m, 2H),3.91 (d, J=13.9 Hz, 1H), 3.87 (s, 3H), 2.50 (t, J=2.6 Hz, 1H), 1.01 (s,9H); MS (ESI+) m/z 538 (M+H)⁺.

Example 91(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 89C, substituting Example 89B for Example 89A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.28 (s, 1H), 7.55 (s, 2H), 7.26-7.13 (m, 3H), 7.10 (d,J=6.9 Hz, 1H), 5.19 (d, J=6.2 Hz, 1H), 4.81 (s, 1H), 4.36-4.20 (m, 2H),3.88 (s, 4H), 3.79 (d, J=12.0 Hz, 1H), 2.58 (s, 1H), 1.82-1.27 (m, 7H),1.01 (d, J=3.6 Hz, 9H); MS (ESI+) m/z 565.1 (M+H)⁺.

Example 92(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 92A 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

Core 12 (1.32 g, 3.66 mmol) was dissolved in dichloromethane (10 mL) andtrimethylamine (2 mL, 14.35 mmol) was added, followed by isopropylchloroformate (2M in toluene, 7 mL, 14 mmol). The reaction was stirredat ambient temperature for 4 hours, at which point it was complete. Thereaction was diluted with dichloromethane (50 mL) and washed with 1Maqueous HCl (2×50 mL) and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated to provide the crude product. Theresidue was purified by silica gel chromatography (5% ethyl acetate indichloromethane) to provide the title compound (1.3 g, 99%). ¹H NMR (400MHz, DMSO-d₆, 120° C.) δ ppm 7.74 (dd, J=7.5, 1.7 Hz, 1H), 7.16-7.04 (m,2H), 6.98 (dd, J=7.4, 1.6 Hz, 1H), 5.88 (d, J=8.5 Hz, 1H), 5.62 (dd,J=8.5, 2.1 Hz, 1H), 4.72 (hept, J=6.2 Hz, 0H), 4.51 (d, J=3.0 Hz, 1H),4.23 (q, J=7.1 Hz, 2H), 2.98 (t, J=2.6 Hz, 1H), 2.10 (ddd, J=13.6, 8.3,5.5 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.14 (d, J=6.2 Hz, 4H), 1.04-0.79(m, 16H). MS (ESI+) m/z 447 (M+H)⁺.

Example 92B 2-ethyl 1-isopropyl(2S,3R,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 92A (875 mg, 1.96 mmol) was dissolved in 22 mL of ethanol andthe solution was heated to 75° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (2.063 g, 5.48 mmol) in 44mL of 6M aqueous HCl and adding Zn (3.882 g, 54.4 mmol) in portionswhile cooling in an ice bath. The suspension was stirred until all Zndissolved, leaving a brilliant blue solution. The CrCl₂ solution wastransferred via cannula over 15 minutes to the mixture of startingmaterial and heating was continued for 16 hours. The temperature wasmaintained between 70° C. and 75° C. during the addition. The reactionmixture was continuously heated between 75° C. and 80° C. overnight,cooled to room temperature, diluted with water, and extracted withdichloromethane (3×100 mL). The combined extracts were washed withbrine, dried over sodium sulfate, filtered, and concentrated. The cruderesidue was dissolved in ethanol (6 mL). A separate solution ofHCl/ethanol was prepared by addition of 1 mL of acetyl chloride to 4 mLof ethanol at 0° C., and poured into the reaction flask and heated to45° C. for 1 hour. The reaction mixture was concentrated in vacuo andloaded onto a 40 g silica gel column, eluting with 5% ethyl acetate indichloromethane to provide the title compound (366.7 mg, 44%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.68 (dd, J=7.3, 1.8 Hz, 1H),7.18-7.05 (m, 3H), 5.63 (s, 1H), 4.69 (heptd, J=6.1, 2.1 Hz, 1H), 4.59(dd, J=5.0, 1.0 Hz, 1H), 4.24 (qt, J=7.1, 1.4 Hz, 2H), 2.61 (d, J=5.0Hz, 1H), 2.13 (ddd, J=13.8, 8.5, 5.4 Hz, 1H), 1.27 (td, J=7.1, 0.9 Hz,3H), 1.06 (d, J=1.0 Hz, 12H), 0.96-0.83 (m, 5H), 0.83-0.74 (m, 1H), 0.53(dqt, J=8.7, 3.5, 1.6 Hz, 1H); MS (ESI+) m/z 416 (M+H)⁺.

Example 92C 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 92B (333.4 mg, 0.802 mmol) was dissolved in ethanol (5 mL), andthe reaction was cooled to 0° C. Sodium borohydride (51.2 mg, 1.353mmol) was added and the reaction was stirred at 0° C. for 1 hour, andwarmed to ambient temperature for another 1 hour. The solvent wasremoved in vacuo and the residue was extracted with ethyl acetate (50mL) and washed with saturated aqueous NaHCO₃ (50 mL) and brine (50 mL),dried over Na₂SO₄, filtered and concentrated to provide crude product,which was purified by silica gel chromatography (5% ethyl acetate indichloromethane) to provide the title compound (201.3 mg, 60%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.89-7.82 (m, 1H), 7.11-7.03 (m, 2H),7.02-6.95 (m, 1H), 5.61 (d, J=0.9 Hz, 0H), 5.47 (d, J=6.2 Hz, 1H), 4.60(p, J=6.2 Hz, 1H), 4.43 (dd, J=6.3, 2.9 Hz, 1H), 4.30 (d, J=3.7 Hz, 1H),4.18 (q, J=7.1 Hz, 2H), 2.29 (t, J=3.3 Hz, 1H), 2.02-1.90 (m, 1H), 1.26(t, J=7.1 Hz, 3H), 1.04-0.97 (m, 12H), 0.96-0.78 (m, 5H), 0.74 (dtd,J=9.5, 5.5, 3.9 Hz, 1H), 0.55 (dtd, J=9.1, 5.6, 3.5 Hz, 1H); MS (ESI+)m/z 418 (M+H)⁺.

Example 92D 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 92D (98.2 mg, 0.235 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (102.3 mg, 0.380mmol) were dissolved in dimethylformamide (1 mL). The reaction wascooled to 0° C., potassium tert-butoxide (1M in tetrahydrofuran, 0.30mL, 0.30 mmol) was added dropwise, and the reaction was stirred atambient temperature for 1 hour. The reaction was quenched by theaddition of 1M aqueous HCl (0.1 mL) and was purified by silica gelchromatography (5% to 100% ethyl acetate) to provide the title compound(65.4 mg, 46%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.27 (s, 1H),7.95 (dd, J=6.7, 2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.01 (tt, J=7.3,5.4 Hz, 2H), 6.93 (dd, J=6.8, 2.3 Hz, 1H), 5.58 (d, J=5.7 Hz, 1H), 4.63(hept, J=6.2 Hz, 1H), 4.41 (d, J=2.0 Hz, 1H), 4.31 (s, 1H), 4.29 (d,J=8.2 Hz, 1H), 3.91-3.84 (m, 4H), 3.21 (dq, J=12.9, 6.6 Hz, 1H),2.57-2.50 (m, 1H), 2.01-1.91 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.07-0.99(m, 12H), 0.95-0.78 (m, 5H), 0.63-0.52 (m, 2H); MS (ESI+) m/z 607(M+H)⁺.

Example 92E(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 92D (55.1 mg, 0.091 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction mixturewas quenched by the addition of 1M aqueous HCl (0.5 mL) and was purifiedby silica gel chromatography (ethyl acetate) to provide the titlecompound (51.7 mg, 98%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.27(s, 1H), 7.95 (dd, J=6.7, 2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.01 (tt,J=7.3, 5.4 Hz, 2H), 6.93 (dd, J=6.8, 2.3 Hz, 1H), 5.58 (d, J=5.7 Hz,1H), 4.63 (hept, J=6.2 Hz, 1H), 4.41 (d, J=2.0 Hz, 1H), 4.31 (s, 1H),4.29 (d, J=8.2 Hz, 1H), 3.91-3.84 (m, 4H), 2.57-2.50 (m, 1H), 2.01-1.91(m, 1H), 1.07-0.99 (m, 12H), 0.95-0.78 (m, 5H), 0.63-0.52 (m, 2H); MS(ESI+) m/z 579 (M+H)⁺.

Example 93(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 93A 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 87C (94.0 mg, 0.224 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (92.3 mg, 0.360 mmol)were dissolved in dimethylformamide (1.1 mL). The reaction was cooled to0° C., then potassium tert-butoxide (1M in tetrahydrofuran, 0.30 mL,0.30 mmol) was added dropwise and the reaction was stirred at ambienttemperature for 1 hour. The reaction mixture was quenched by theaddition of 1M aqueous HCl (0.1 mL) and was purified by silica gelchromatography (5% to 100% ethyl acetate in heptanes) to provide thetitle compound (95.7 mg, 72%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm7.94 (dd, J=8.1, 1.4 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.18 (dd, J=7.9,1.5 Hz, 1H), 7.16-7.10 (m, 1H), 7.07-6.98 (m, 1H), 6.88 (d, J=2.4 Hz,1H), 5.25 (d, J=5.6 Hz, 1H), 4.63 (hept, J=6.2 Hz, 1H), 4.43 (d, J=2.1Hz, 1H), 4.23-4.06 (m, 6H), 3.73 (s, 3H), 3.37-3.14 (m, 2H), 2.31-2.17(m, 2H), 2.03-1.80 (m, 4H), 1.25 (d, J=6.8 Hz, 3H), 1.21-1.12 (m, 6H),1.02 (d, J=1.8 Hz, 12H), 0.82 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 595(M+H)⁺.

Example 93B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 93A (82.7 mg, 0.139 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL) and was purified bysilica gel chromatography (5 to 100% ethyl acetate in dichloromethane)to provide the title compound (66.4 mg, 84%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 8.00 (dd, J=7.9, 1.4 Hz, 1H), 7.77-7.72 (m, 1H),7.21-7.09 (m, 2H), 7.02 (ddd, J=8.4, 7.1, 1.6 Hz, 1H), 6.86 (d, J=2.4Hz, 1H), 5.24 (d, J=5.7 Hz, 1H), 4.63 (p, J=6.2 Hz, 1H), 4.38 (d, J=2.1Hz, 1H), 4.22-4.13 (m, 2H), 3.81-3.72 (m, 4H), 3.30 (p, J=8.5 Hz, 1H),3.21 (p, J=6.8 Hz, 1H), 2.50 (t, J=1.4 Hz, 1H), 2.29-2.13 (m, 2H),2.03-1.78 (m, 4H), 1.25 (d, J=6.7 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H),1.07-0.96 (m, 12H), 0.81 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 567 (M+H)⁺.

Example 94(2S,3R,4R,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 95F, substituting2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine, and Example 95E forExample 95D. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.33 (ddd, J=7.4, 1.9, 0.8Hz, 1H), 8.03 (dd, J=4.9, 1.9 Hz, 1H), 7.64-7.58 (m, 2H), 7.18 (d, J=8.4Hz, 1H), 6.91 (dd, J=7.4, 4.9 Hz, 1H), 5.51-5.44 (m, 1H), 5.11 (s, 1H),5.03 (d, J=13.1 Hz, 1H), 4.71-4.65 (m, 1H), 4.62 (d, J=13.1 Hz, 1H),4.31 (d, J=11.3 Hz, 1H), 3.97 (d, J=3.6 Hz, 1H), 3.89 (s, 3H), 3.74 (d,J=9.1 Hz, 1H), 2.10-2.03 (m, 1H), 1.40 (d, J=6.1 Hz, 3H), 1.34 (d, J=6.2Hz, 3H), 1.11-1.01 (m, 6H), 0.99 (s, 9H); MS (ESI−) m/z 595.3 (M−H).

Example 95(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 95A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-nitropyrrolidine-1,2-dicarboxylate

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-nitropyrrolidine-2-carboxylate(Core 7) (2.00 g, 5.27 mmol) and triethylamine (5.88 mL, 42.2 mmol) indichloromethane (10 mL) was added isopropyl carbonochloridate (3.88 g,31.6 mmol) drop wise at ambient temperature. The mixture was stirred for2 hours, and dichloromethane (2 0 mL) and water (10 mL) added. Theorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification of the residue via chromatography, elutingwith ethyl acetate in heptanes provided the title compound (2.26 g, 92%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.04 (dd, J=5.0, 1.8 Hz, 2H), 6.82(dd, J=7.4, 5.0 Hz, 1H), 5.50 (d, J=8.0 Hz, 1H), 5.37 (dd, J=12.7, 6.8Hz, 2H), 4.88 (s, 1H), 4.70 (s, 1H), 4.34 (qd, J=7.2, 2.3 Hz, 2H), 2.94(t, J=1.6 Hz, 1H), 1.43-1.33 (m, 9H), 1.15-1.123 (m, 6H), 1.08 (s, 9H);MS (ESI+) m/z 466 (M+H)⁺.

Example 95B (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-hydroxypyridin-3-yl)-4-oxopyrrolidine-1,2-dicarboxylate

To potassium dichromate (6.07 g, 20.62 mmol) in 6M aqueous HCl (60 mL)was added zinc (6.75 g, 103 mmol) under N₂ atmosphere. After thecomplete dissolution of zinc, providing a clear light blue solution, theformed chromium(II) chloride was transferred to the refluxing solutionof Example 95A (1.6 g, 3.44 mmol) in ethanol (60 mL) under N₂. Thereaction mixture was refluxed at 85° C. for 16 hours. LC/MS indicatedthe reaction was finished and showed two peaks, one was desired titlecompound and another was saponified acid. The mixture was cooled,concentrated to half of its volume, and extracted with ethyl acetate (60mL×3). The combined organic phase was washed with saturated aqueousNaHCO₃ solution and brine, dried over MgSO₄, filtered, and concentrated.To the residue in ethanol (5 mL) was added a prepared solution of acetylchloride (1 mL) in ethanol (5 mL) slowly. The mixture was heated at 60°C. for 2 hours. The solvent was removed and the residue was dissolved indichloromethane (30 mL) and washed with NaHCO₃ and brine, dried overMgSO₄, filtered, and concentrated. The residue was purified viachromatography, eluting with methanol in ethyl acetate at 0-20% gradientto provide the title compound (1.05 g, 78%). LC/MS (APCI+) m/z 393.17(M+H)⁺.

Example 95C (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-oxopyrrolidine-1,2-dicarboxylate

To the mixture of Example 95B (500 mg, 1.274 mmol) and silver carbonate(CAS#534-16-7) (703 mg, 2.55 mmol) in CHCl₃ (10 mL) was added2-iodopropane (CAS#75-30-9) (325 mg, 1.911 mmol) dropwise. The mixturewas refluxed for 3 hours, and was stirred at ambient temperatureovernight to complete the reaction. The reaction mixture was filteredand the solid was washed with dichloromethane (5 mL×2). The combinedorganics were washed with brine and concentrated to provide the titlecompound (550 mg, 99% yield) which used in next step without furtherpurification. LC/MS (APCI+) m/z 435.4 (M+H)⁺.

Example 95D (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylateand Example 95E (2S,3R,4R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

To Example 95C (180 mg, 0.414 mmol) in ethanol (5 mL) cooled with anice-bath was added sodium borohydride (31.3 mg, 0.828 mmol) portionwise.The mixture was stirred in ice-bath for 30 minutes and was allowed towarm to ambient temperature. LC/MS indicated the conversion was finishedand showed two diastereoisomeric peaks with ratio about 2:1. Aqueoussaturated NH₄Cl (1 mL) and dichloromethane (20 mL) were added. Themixture was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography, eluting withethyl acetate/methanol (9:1) in heptane. The first eluent was Example95E (2S,3R,4R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate(60 mg, 33.2% yield); and the second eluent was the title compoundExample 95D (121 mg, 66.5% yield). LC/MS (APCI+) m/z 437.5 (M+H)⁺.

Example 95F(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-(isopropoxycarbonyl)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylicacid

To Example 95D (51 mg, 0.117 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (30 mg, 0.117 mmol) indimethylformamide (1 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (19.71 mg, 0.176 mmol, 0.18 mL, 1.0 M intetrahydrofuran) was added drop wise. The mixture was stirred in anice-bath for 30 minutes, and was allowed to warm to room temperature.Methanol (1.5 mL) and 6M aqueous LiOH (0.5 mL) were added. The mixturewas stirred at 50° C. overnight, and adjusted to pH 1˜2 with theaddition of 2M aqueous HCl. The reaction mixture was concentrated, andthe residue was taken up in dichloromethane and filtered through asyringe filter. The filtrate was purified via chromatography, on a 4 gsilica gel cartridge, eluting with methanol in dichloromethane at 0-20%gradient to provide the title compound (35 mg, 51.2% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.13 (dd, J=7.4, 1.9 Hz, 1H), 7.93 (dd, J=4.9, 2.0Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 6.86-6.79 (m, 2H), 5.23 (p, J=6.2 Hz,1H), 5.16 (d, J=6.0 Hz, 1H), 4.67 (hept, J=6.2 Hz, 1H), 4.37 (d, J=2.5Hz, 1H), 4.28 (d, J=13.2 Hz, 1H), 4.22 (dd, J=6.0, 1.6 Hz, 1H), 3.95 (d,J=13.1 Hz, 1H), 3.76 (s, 3H), 3.32 (hept, J=6.2 Hz, 1H), 2.49-2.48 (m,1H), 2.29-2.19 (m, 2H), 2.01-1.83 (m, 4H), 1.29 (d, J=6.1 Hz, 3H), 1.21(d, J=6.1 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 0.99 (s, 9H), 0.93 (d, J=6.2Hz, 3H); MS (ESI+) m/z 584.1 (M+H)⁺.

Example 96(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 96A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

Core 11 (12.3 g, 33.9 mmol) was dissolved in toluene (120 mL) andsaturated aqueous sodium bicarbonate (120 mL) was added. Allylchloroformate (3.98 mL, 37.3 mmol) was added, and the reaction mixturewas stirred at ambient temperature for 20 minutes, at which point LC/MSindicated complete conversion of the starting material. The reaction wasdiluted with methyl tert-butyl ether (70 mL) and the layers wereseparated. The organic layer was washed with 1M aqueous HCl (2×30 mL),1M aqueous NaOH (2×30 mL) and brine (30 mL). The organic layer was driedover sodium sulfate, filtered, concentrated, and purified via flashchromatography, eluting with 0:100 to 30:70 methyl tert-butylether:heptanes over 30 minutes on a 330 g silica gel column to provide12.3 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm7.86 (dd, J=8.0, 1.2 Hz, 1H), 7.32-7.14 (m, 2H), 7.05 (ddd, J=8.4, 6.5,2.1 Hz, 1H), 5.72 (d, J=9.0 Hz, 1H), 5.65 (ddd, J=17.2, 10.7, 5.3 Hz,1H), 5.53 (dd, J=8.9, 3.6 Hz, 1H), 5.08-4.93 (m, 2H), 4.55 (d, J=4.3 Hz,1H), 4.41 (d, J=5.2 Hz, 2H), 4.27 (qd, J=7.0, 0.9 Hz, 2H), 3.24 (p,J=6.7 Hz, 1H), 3.14-3.05 (m, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.27 (d, J=6.6Hz, 3H), 1.19 (d, J=6.7 Hz, 3H), 1.03 (s, 9H); MS (ESI+) m/z 447.3(M+H)⁺.

Example 96B (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 96A (11.2 g, 25.08 mmol) was dissolved in ethanol (226 mL) andthe solution was heated to 75° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (23.59 g, 62.7 mmol) inaqueous hydrochloric acid, (6M, 452 mL) and adding Zn (44.3 g, 667 mmol)in portions while cooling in an ice bath, maintaining an internaltemperature below 35° C. The resulting suspension was stirred at ambienttemperature for 30 minutes after removing the flask from the ice bath,leaving a blue solution of CrCl₂, which was added via cannula over 20minutes to the reaction flask containing the solution of the startingmaterial in ethanol at 75° C. Heating was continued at 85° C. for 36hours. The flask was cooled to ambient temperature, and the organicmaterial was extracted with dichloromethane (3×200 mL). The combinedextracts were dried over sodium sulfate, filtered, and concentrated. Thematerial was redissolved in an anhydrous solution of HCl in ethanol thatwas prepared by the addition of acetyl chloride (8.9 mL, 125 mmol) to100 mL of ethanol via syringe while cooling in an ice-water bath. Theresulting solution was heated to 45° C. for 1 hour, at which pointcomplete re-esterification had occurred. The reaction mixture wasconcentrated and the crude material was partitioned between saturatedaqueous sodium bicarbonate and methyl tert-butyl ether (300 mL each).The organic extracts were dried over sodium sulfate, filtered, andconcentrated to provide (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate(10 g) as an inseparable mixture with unreacted oxime. The mixture wasused in the next step without additional purification.

Example 96C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 96B (10 g, 24.07 mmol) was dissolved in 100 mL of ethanol andsodium borohydride (0.910 g, 24.07 mmol) was added in one portion aftercooling to −5° C. The reaction was complete in 10 minutes at thistemperature, as indicated by LC/MS. Acetone (10 mL) was added to quenchthe excess borohydride, and the reaction mixture was stirred at the sametemperature for 15 minutes. The flask was warmed to ambient temperature,concentrated in vacuo, and partitioned between methyl tert-butyl etherand saturated sodium bicarbonate (100 mL each). The organic extractswere concentrated in vacuo to provide crude material, which was purifiedvia flash chromatography, eluting with 0:100 to 30:70 methyl tert-butylether:heptanes over 40 minutes on a 220 g silica gel column to provide5.5 g of the desired diastereomer (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropylphenyl)pyrrolidine-1,2-dicarboxylateas an inseparable mixture with the oxime from the previous step. ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.90 (dd, J=7.8, 1.5 Hz, 1H), 7.20(ddd, J=7.7, 4.4, 1.5 Hz, 1H), 7.13 (tdd, J=7.6, 2.8, 1.5 Hz, 1H), 7.05(ddd, J=8.9, 7.2, 1.5 Hz, 1H), 5.70-5.59 (m, 1H), 5.22 (d, J=6.6 Hz,1H), 5.04-4.84 (m, 2H), 4.35 (m, 3H), 4.30 (d, J=4.6 Hz, 1H), 4.24-4.14(m, 2H), 3.75 (br s, 1H), 3.19 (dt, J=13.6, 6.9 Hz, 1H), 2.37-2.25 (m,1H), 1.26 (d, J=5.7 Hz, 3H), 1.24 (t, J=4 Hz, 3H), 1.20 (d, J=5.7 Hz,3H), 1.00 (s, 9H); MS (ESI+) m/z 418.1 (M+H)⁺.

Example 96D (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 96C (1.75 g, 3.14 mmol) was dissolved in 1.2 mL of drydimethylformamide. After cooling to 0° C. in an ice bath, potassiumtert-butoxide (1M in tetrahydrofuran, 4.6 mL, 4.6 mmol) solution wasadded dropwise, followed immediately by addition of3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (1.36 g, 5.0 mmol)dropwise via syringe. LC/MS after 10 minutes showed complete conversionof the starting alcohol. The reaction was quenched with saturatedaqueous ammonium chloride (10 mL) and extracted with methyl tert-butylether (3×20 mL). The combined organic extracts were concentrated invacuo and purified via flash chromatography, eluting on a 120 g silicagel column with 0:100 to 20:80 methyl tert-butyl ether:heptanes over 20minutes to provide 955 mg of the title compound. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 8.33-8.21 (m, 1H), 7.92 (dd, J=7.9, 1.4 Hz, 1H),7.17 (dt, J=5.7, 1.5 Hz, 2H), 7.10 (td, J=7.5, 1.4 Hz, 1H), 7.01-6.93(m, 1H), 5.66 (ddt, J=16.2, 10.4, 5.1 Hz, 1H), 5.33 (d, J=5.7 Hz, 1H),5.04-4.87 (m, 2H), 4.50 (d, J=2.2 Hz, 1H), 4.39 (d, J=5.2 Hz, 2H),4.29-4.22 (m, 2H), 4.13 (qd, J=7.1, 1.2 Hz, 2H), 3.86 (s, 3H), 3.78 (d,J=13.8 Hz, 1H), 3.24 (p, J=6.8 Hz, 1H), 2.52 (t, J=1.6 Hz, 1H), 1.23 (d,J=6.7 Hz, 3H), 1.19 (d, J=7.0 Hz, 3H), 1.15 (t, J=8 Hz, 3H), 1.05 (s,9H); MS (ESI+) m/z 607.0 (M+H)⁺.

Example 96E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 96D (850 mg, 1.401 mmol) and1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (438 mg, 2.80 mmol) weredissolved in 14 mL of a 1:1 mixture of dichloromethane and ethyl acetatethat had been degassed for 5 minutes. Palladiumtetrakis(triphenylphosphine)palladium (16.19 mg, 0.014 mmol) was added,and the reaction mixture was stirred at ambient temperature for 15minutes, at which point the reaction was complete as indicated by LC/MS.The reaction mixture was diluted with methyl tert-butyl ether (50 mL)and stirred with 10 mL of 10% aqueous sodium carbonate solution for 10minutes. The organic layer was washed with brine and concentrated invacuo to provide crude material. The crude material was purified viaflash chromatography, eluting with 0:100 to 30:70 methyl tert-butylether:heptanes over 20 minutes on a 40 g silica gel column to provide623 mg of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.34-8.26 (m, 1H), 7.63 (dd,J=7.9, 1.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.22 (dd, J=7.8, 1.5 Hz,1H), 7.14 (td, J=7.5, 1.4 Hz, 1H), 7.02 (td, J=7.6, 1.4 Hz, 1H), 4.42(d, J=4.5 Hz, 1H), 4.22 (d, J=13.6 Hz, 1H), 4.15 (q, J=8 Hz, 2H), 3.96(dd, J=4.6, 1.8 Hz, 1H), 3.85 (s, 3H), 3.77 (d, J=13.7 Hz, 1H), 3.65 (d,J=6.5 Hz, 1H), 3.24 (p, J=6.8 Hz, 1H), 2.42 (dd, J=6.5, 1.8 Hz, 1H),1.22 (t, J=8 Hz, 3H), 1.21 (br s, 3H), 1.19 (br s, 3H) 1.00 (s, 9H); MS(ESI+) m/z 523.1 (M+H)⁺.

Example 96F (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylateand Example 96G (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((R)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

Example 96D (370 mg, 0.71 mmol) was dissolved in dichloromethane (7.1mL) and triethylamine (0.30 mL, 2.1 mmol) was added. After cooling in anice bath to <10° C., a solution of freshly-preparedtetrahydro-2H-pyran-2-carbonyl chloride (158 mg, 1.062 mmol) was addeddropwise, and the reaction was complete as soon as the addition wasdone, as indicated by LC/MS. The reaction mixture was diluted withmethyl tert-butyl ether (10 mL) and 1M aqueous HCl (10 mL) was added.The layers were separated, and the organic layer was washed with 1Maqueous HCl (2×5 mL) and brine (10 mL), dried over sodium sulfate,filtered, and concentrated in vacuo to provide a crude residue. Thecrude material was purified via flash chromatography, eluting with 0:100to 20:80 methyl tert-butyl ether:heptanes over 5 minutes then isocratic20:80 methyl tert-butyl ether:heptanes for 40 minutes on an 80 g silicagel column to provide Example 96F (144 mg) as the first-elutingdiastereomer and Example 96G (120 mg) as the second-elutingdiastereomer. Example 96F (first eluting)¹H NMR (400 MHz, DMSO-d₆, 120°C.) δ ppm 8.33-8.19 (m, 1H), 8.00 (dd, J=7.9, 1.5 Hz, 1H), 7.24 (d,J=7.6 Hz, 1H), 7.15 (s, 2H), 7.03 (d, J=7.9 Hz, 1H), 5.61 (d, J=0.8 Hz,1H), 4.74 (d, J=1.8 Hz, 1H), 4.29 (d, J=13.8 Hz, 1H), 4.24 (d, J=5.7 Hz,1H), 4.09 (qd, J=7.1, 2.9 Hz, 2H), 3.86 (s, 3H), 3.80 (d, J=13.9 Hz,1H), 3.73 (s, 1H), 3.24 (p, J=6.8 Hz, 1H), 3.18-2.93 (m, 1H), 2.45 (d,J=1.7 Hz, 2H), 1.74-1.61 (m, 1H), 1.54 (t, J=10.7 Hz, 2H), 1.37 (s, 3H),1.30 (d, J=6.7 Hz, 3H), 1.16 (d, J=6.6 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H),1.05 (s, 9H); MS (ESI+) m/z 635.1 (M+H)⁺. Example 96G (second eluting)¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.35-8.15 (m, 1H), 7.80 (s, 1H),7.22-6.88 (m, 4H), 5.40 (d, J=5.6 Hz, 1H), 4.97 (s, 1H), 4.28 (d, J=13.8Hz, 1H), 4.21 (d, J=5.5 Hz, 1H), 4.19-4.08 (m, 2H), 3.86 (s, 3H), 3.79(d, J=13.8 Hz, 1H), 3.24 (hept, J=6.6 Hz, 1H), 2.59 (s, 1H), 1.90-1.85(br s, 3H), 1.85-1.35 (m, 6H), 1.29-1.22 (m, 3H), 1.19 (dd, J=6.6, 1.1Hz, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.05 (s, 9H); MS (ESI+) m/z 635.1(M+H)⁺.

Example 96H(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 96F (140 mg, 0.22 mmol) was dissolved in a mixture of 0.9 mL oftetrahydrofuran, 0.9 mL of water, and 0.45 mL of methanol. Lithiumhydroxide hydrate (93 mg, 2.21 mmol) was added, and the reaction mixturewas heated to 50° C. for 16 hours. The reaction mixture was cooled toroom temperature, diluted with dichloromethane (10 mL), acidified with1M aqueous HCl to pH=3, and extracted with 3×5 mL dichloromethane. Theorganic extracts were combined, dried over sodium sulfate, filtered, andconcentrated in vacuo to provide Example 96H. X-ray confirmation of theabsolute stereochemistry confirmed the identity of the title compound.¹H NMR (400 MHz, DMSO-d₆, 120° C.) 6 ppm 8.33-8.18 (m, 1H), 8.06 (dd,J=8.0, 1.3 Hz, 1H), 7.32-6.93 (m, 4H), 5.63 (s, 1H), 4.71 (d, J=1.7 Hz,1H), 4.33 (d, J=14.0 Hz, 1H), 4.24 (d, J=5.8 Hz, 1H), 3.87 (s, 3H), 3.84(d, J=8.0 Hz, 1H) 3.75 (d, J=11.2 Hz, 1H), 3.24 (p, J=6.8 Hz, 1H),3.20-2.80 (br s, 2H), 2.52 (d, J=1.7 Hz, 1H), 1.73-1.22 (m, 6H), 1.30(d, J=6.7 Hz, 3H), 1.13 (d, J=6.7 Hz, 3H), 1.04 (s, 9H); MS (ESI+) m/z607.1 (M+H)⁺.

Example 97(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 96G (120 mg, 0.189 mmol) was dissolved in a mixture of 0.8 mL oftetrahydrofuran, 0.8 mL of water, and 0.4 mL of methanol in a 20-mLscintillation vial. Lithium hydroxide hydrate (79 mg, 1.9 mmol) wasadded, and the reaction mixture was heated to 50° C. for 16 hours in aheating block. The vial was cooled to room temperature, diluted withdichloromethane (5 mL), acidified with 1M aqueous HCl to pH=3, andextracted into dichloromethane (3×5 mL). The combined organic extractswere dried over sodium sulfate, filtered, and concentrated in vacuo toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm8.29-8.20 (m, 1H), 7.85 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.13-7.00 (m,2H), 6.94 (t, J=7.5 Hz, 1H), 5.39 (d, J=5.8 Hz, 1H), 4.90 (s, 1H), 4.30(d, J=14.0 Hz, 1H), 4.19 (d, J=5.8 Hz, 1H), 3.98 (br s, 1H), 3.86 (s,3H), 3.82 (d, J=14.0 Hz, 1H), 3.82-3.75 (br s, 1H), 3.23 (p, J=6.8 Hz,2H), 2.64 (s, 1H), 1.79 (s, 1H), 1.65-1.35 (m, 5H), 1.26 (d, J=6.7 Hz,3H), 1.16 (d, J=6.8 Hz, 3H), 1.04 (s, 9H); MS (ESI+) m/z 607.1 (M+H)⁺.

Example 98(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 98A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

(S)-Tetrahydrofuran-2-carboxylic acid (0.040 g, 0.344 mmol) was refluxedin thionyl chloride (0.65 mL, 8.96 mmol) for 1 hour, and the mixture wascooled to room temperature and concentrated in vacuo. Excess thionylchloride was chased three times with dichloromethane (1 mL each), andthe residue was treated with a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(Example 96E) 0.180 g, 0.344 mmol) in dichloromethane (1 mL) and withpyridine (0.33 mL, 4.13 mmol). The mixture was stirred at roomtemperature for 2 hours. The reaction mixture was then diluted with 10mL of ethyl acetate and washed with water (3×3 mL) and with brine (3mL). The organic layer was dried over Na₂SO₄, filtered and concentratedin vacuo, and the crude product was used directly in the next reactionwithout further purification. MS (ESI⁺) m/z 621.6 (M+H)⁺.

Example 98B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 98A (0.214 g, 0.344 mmol) and lithium hydroxide (1M aqueous)(3.5 mL, 3.50 mmol) were stirred in tetrahydrofuran (3.5 mL) andmethanol (3.50 mL) overnight at 45° C. After this time, the reactionmixture was carefully acidified to pH 2 with 1N aqueous HCl, and theentire mixture was concentrated in vacuo. Excess moisture was removedazeotropically with acetonitrile, and the residue was subjected tosilica gel chromatography, eluting with 0 to 20%methanol-dichloromethane. The still-impure material thus obtained waspurified further by silica gel chromatography eluting with 5 to 25% 3:1ethyl acetate-ethanol in heptanes to provide the title compound (45.9mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (m, 1H), 8.03 (d, J=7.7 Hz,1H), 7.16 (m, 3H), 7.00 (t, J=7.5 Hz, 1H), 5.65 (m, 1H), 4.69 (d, J=1.9Hz, 1H), 4.37-4.19 (m, 2H), 4.09 (m, 1H), 3.86-3.80 (m, 4H), 3.77-3.48(m, 2H), 3.25 (m, 1H), 2.55 (m, 1H), 2.08-1.63 (m, 4H), 1.24 (d, J=6.7Hz, 3H), 1.15 (d, J=6.7 Hz, 3H), 1.03 (s, 9H); MS (ESI⁺) m/z 593.1(M+H)⁺.

Example 99(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 86 substituting Core 14 for Core 10. ¹H NMR (500 MHz, DMSO-d₆) δppm 8.38 (d, J=2.3 Hz, 1H), 8.27 (s, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.21(td, J=7.2, 3.4 Hz, 2H), 6.94 (d, J=44.3 Hz, 1H), 5.29 (s, 1H), 4.65 (d,J=62.1 Hz, 1H), 4.42 (d, J=14.4 Hz, 1H), 4.35 (d, J=7.6 Hz, 2H), 4.02(d, J=14.4 Hz, 1H), 3.87 (s, 3H), 2.58 (s, 1H), 1.21-1.12 (m, 3H), 1.01(s, 12H); MS (APCI+) m/z 574 (M+H)⁺.

Example 100(2S,3R,4S,5S)-3-tert-butyl-4-[(2-cyclobutyl-5-methoxypyridin-4-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 100A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-nitro-5-phenylpyrrolidine-1,2-dicarboxylate

A solution of Core 5 (30 g, 94 mmol) in toluene (187 mL) was treatedwith triethylamine (32.6 mL, 234 mmol) and was cooled in an ice bath to˜10° C. Isopropyl carbonochloridate (56.2 mL, 112 mmol, 2M solution intoluene) was added at such a rate that the temperature was maintained ator below room temperature during the addition (2-3 minutes). After theaddition was complete, the flask was removed from the cold bath andstirred at room temperature for 45 minutes. The mixture was diluted withethyl acetate and stirred with saturated aqueous sodium bicarbonate for20 minutes. The phases were separated, and the organic layer was washedwith 1M aqueous HCl three times and once with brine. The organic layerwas dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was treated with 50 mL of heptane and stirred vigorously. Themixture was stirred in an ice bath for an additional 30 minutes. Thematerial was collected by filtration, washed with cold heptane, andair-dried to provide the title compound, 35 g (92%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.54-7.47 (m, 2H), 7.28-7.15 (m, 3H), 5.60 (ddd, J=8.9,3.4, 1.0 Hz, 1H), 5.43 (d, J=8.8 Hz, 1H), 4.67 (hept, J=6.2 Hz, 1H),4.50 (d, J=3.8 Hz, 1H), 4.28-4.19 (m, 2H), 2.98 (t, J=3.5 Hz, 1H), 1.29(t, J=7.1 Hz, 3H), 1.10-0.98 (m, 12H), 0.95 (m, 3H); MS (APCI⁺) m/z407.3 (M+H)⁺.

Example 100B (2S,3R,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-oxo-5-phenylpyrrolidine-1,2-dicarboxylate

Example 100A (20 g, 49.2 mmol) was dissolved in ethanol (443 mL), andthe solution was heated to 75° C. A separate solution of chromium(II)chloride was prepared by dissolving pyridinium dichromate (48.1 g, 128mmol) in 6M aqueous hydrochloric acid (887 mL) and adding zinc dust (88g, 1.34 mol) in portions while cooling in an ice bath. The suspensionwas stirred at room temperature for 60 minutes after removing from theice bath, leaving a brilliant blue solution. The solution wastransferred via cannula over 90 minutes to the heated solution ofstarting material, Example 100A. The temperature was maintained between70° C. and 75° C. during the addition. After completion of the addition,the heating was continued between 75° C. and 80° C. for 12 hours, andthe reaction was brought to room temperature. The mixture was pouredinto a separatory funnel and extracted three times with dichloromethane(total 750 mL). The combined extracts were dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was thenredissolved in ethanol (295 mL) and treated with a solution (prepared at0° C.) of acetyl chloride (26.2 mL, 369 mmol) in ethanol (295 mL). Theresulting solution was heated to 40° C. for 90 minutes, and cooled toroom temperature. The solution was concentrated in vacuo to a volume ofapproximately 20 mL and was diluted with methyl tert-butyl ether. Thesolution was poured into a separatory funnel and washed three times with1M aqueous HCl, three times with saturated sodium bicarbonate, and oncewith brine. The solution was dried over sodium sulfate, filtered, andconcentrated in vacuo to provide the crude title compound, 26.84 g. Thetitle compound was used directly in the subsequent reaction. MS (APCI⁺)m/z 376.5 (M+H)⁺.

Example 100C (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate

Example 100B (26.84 g, 71.5 mmol) was dissolved in ethanol (357 mL) in a1 L round bottom flask. After cooling in an acetone-ice bath to ˜−9° C.,sodium borohydride (3.25 g, 86 mmol) was added in portions. After theaddition, the cold bath was allowed to warm to −5° C., and excess sodiumborohydride was quenched by slow addition of acetone (˜5 mL). A delayedexotherm from 0 to 22° C. was noted. After the exotherm had subsided,the mixture continued stirring in the ice bath for another 20 minutesand was concentrated in vacuo to approximately 50 mL. Ethyl acetate (300mL) was added, followed by 200 mL of saturated sodium bicarbonate, andthe entire mixture was then stirred for 30 minutes at room temperature.The phases were separated, and the organic layer was washed with 1Maqueous NaOH (2×100 mL), 1M aqueous HCl (2×100 mL), and brine (100 mL).The organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuo. Heptanes (100 mL) were added, and the mixture washeated to dissolve the material (˜60° C.). The mixture was allowed tocool slowly with stirring. After stirring at room temperature overnight,the solid was collected by filtration, washed with cold heptanes, anddried under vacuum. Silica gel chromatography of the crude material,eluting with 0 to 20% methyl tert-butyl ether-heptanes, provided thetitle compound, 18.7 g (67% yield over two steps). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.54-7.46 (m, 2H), 7.22 (m, 1H), 7.23-7.10 (m, 2H), 4.82(d, J=6.7 Hz, 1H), 4.62 (hept, J=6.2 Hz, 1H), 4.31 (ddd, J=6.7, 5.3, 4.4Hz, 1H), 4.25-4.09 (m, 3H), 3.84 (m, 1H), 2.24 (m, 1H), 1.24 (t, J=7.1Hz, 3H), 1.04 (d, J=6.2 Hz, 3H), 0.98 (s, 9H), 0.90 (d, J=6.2 Hz, 3H);MS (ESI⁺) m/z 378.0 (M+H)⁺.

Example 100D 2-bromo-4-(bromomethyl)-5-methoxypyridine

To a solution of 2-bromo-5-methoxy-4-methylpyridine (1.00 g, 4.95 mmol)in CCl₄ (8 mL) was added N-bromosuccinimide (0.969 g, 5.44 mmol) and(E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.012 g, 0.074mmol). The reaction was stirred at 80° C. for 2 hours, and cooled in anice bath and filtered through diatomaceous earth. The solution wasconcentrated, and the crude product was purified with silica gelchromatography (5-50% ethyl acetate/heptanes, eluent) to provide thetitle compound, 0.280 g (20% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.04(s, 1H), 7.46 (s, 1H), 4.41 (s, 2H), 4.00 (s, 3H).

Example 100E (2S,3R,4S,5S)-2-ethyl 1-isopropyl4-((2-bromo-5-methoxypyridin-4-yl)methoxy)-3-(tert-butyl)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 100C (0.380 g, 1.007 mmol) and Example 100D (0.280 g, 0.997mmol) were dissolved in dry dimethylformamide (2.2 mL), and theresulting solution was cooled in an ice bath. A 1M solution of potassium2-methylpropan-2-olate in tetrahydrofuran (1.6 mL, 1.6 mmol) was addeddropwise over 10 minutes. The mixture was acidified with 1M aqueous HCl(40 drops) and warmed to room temperature. The mixture was diluted with15 mL of water and 75 mL of methyl tert-butyl ether. The aqueous layerwas removed, and the organics were washed with water and brine and thenconcentrated in vacuo. Silica gel chromatography (5 to 100% ethylacetate-heptanes, eluent) provided the title compound, 85 mg (15%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.92 (s, 1H), 7.59-7.51 (m, 2H),7.25-7.10 (m, 3H), 6.71 (d, J=1.2 Hz, 1H), 5.00 (d, J=6.1 Hz, 1H), 4.65(p, J=6.2 Hz, 1H), 4.37 (d, J=3.0 Hz, 1H), 4.29-4.21 (m, 2H), 4.15 (qd,J=7.1, 2.9 Hz, 2H), 3.86 (dd, J=14.6, 1.1 Hz, 1H), 3.76 (s, 3H), 2.44(t, J=2.6 Hz, 1H), 1.20 (t, J=7.1 Hz, 3H), 1.05 (d, J=6.2 Hz, 3H), 1.01(s, 9H), 0.90 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 577 (M+H)⁺.

Example 100F (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((2-cyclobutyl-5-methoxypyridin-4-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 100E (84 mg, 0.145 mmol) in tetrahydrofuran (1.45 mL) wastreated withdichloro[4,5-dichloro-1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl, 12.5 mg, 0.015 mmol), followed by dropwise addition ofcyclobutylzinc(II) bromide (0.5M in tetrahydrofuran) (0.35 mL, 0.175mmol) at room temperature. After 30 minutes, an additional amount ofcyclobutylzinc(II) bromide solution was added, (0.5M in tetrahydrofuran,0.23 mL, 0.116 mmol), and the reaction continued to stir at roomtemperature for 2 hours. The reaction mixture was then quenched withsaturated aqueous NH₄Cl solution, and the solvent was then evaporatedunder a stream of nitrogen. The crude product was purified by silica gelchromatography using 5-50% ethyl acetate/heptanes as the eluent toobtain the title compound, 71 mg (88% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.05 (s, 1H), 7.61-7.51 (m, 2H), 7.25-7.10 (m, 3H), 6.52 (s, 1H),5.00 (d, J=6.1 Hz, 1H), 4.64 (p, J=6.2 Hz, 1H), 4.36 (d, J=3.1 Hz, 1H),4.30-4.18 (m, 2H), 4.11 (qd, J=7.1, 2.7 Hz, 2H), 3.89 (d, J=13.8 Hz,1H), 3.73 (s, 3H), 3.40 (p, J=8.4 Hz, 1H), 2.27-2.06 (m, 4H), 1.97 (dq,J=10.7, 8.7 Hz, 1H), 1.83 (dddd, J=9.9, 8.9, 7.9, 4.1 Hz, 1H), 1.16 (t,J=7.1 Hz, 3H), 1.05 (d, J=6.2 Hz, 3H), 1.00 (s, 9H), 0.89 (d, J=6.3 Hz,3H), 0.85 (dt, J=7.5, 2.8 Hz, 1H); MS (ESI+) m/z 552 (M+H)⁺.

Example 100G(2S,3R,4S,5S)-3-tert-butyl-4-[(2-cyclobutyl-5-methoxypyridin-4-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 100F (0.054 g, 0.098 mmol) in tetrahydrofuran (0.78 mL) andmethanol (0.78 mL) was treated with lithium hydroxide (1M aqueous) (0.78mL, 0.780 mmol), and the reaction was stirred at 45° C. overnight. Anadditional amount of 1M aqueous LiOH was added (0.2 mL), and stirringwas continued at 50° C. for 6 hours and at room temperature for 3 days.After this time, the pH was adjusted carefully to pH 2 with 1N aqueousHCl, and the whole mixture was concentrated in vacuo. The residue wasdried azeotropically with acetonitrile, and the resulting material waspurified by silica gel chromatography, eluting with 5 to 25% 3:1 ethylacetate/ethanol—heptanes to obtain the title compound, 43 mg (84%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.04 (s, 1H), 7.61 (d, J=7.4 Hz,2H), 7.23-7.10 (m, 3H), 6.49 (s, 1H), 4.97 (d, J=6.4 Hz, 1H), 4.66-4.58(m, 1H), 4.24 (m, 2H), 4.16 (dd, J=6.3, 2.4 Hz, 1H), 3.90 (d, J=13.8 Hz,1H), 3.73 (s, 3H), 3.39 (m, 1H), 2.52 (m, 1H), 2.22-1.81 (m, 6H), 1.05(d, J=6.3 Hz, 3H), 0.98 (s, 9H), 0.87 (d, J=6.2 Hz, 3H); MS (ESI⁺) m/z525.3 (M+H)⁺.

Example 101(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 43, substituting Example 86D for Example 40A, andcyclobutylzinc(II) bromide for cyclohexylzinc bromide in Example 43A. ¹HNMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.24 (d, J=2.1 Hz,1H), 8.07 (d, J=7.8 Hz, 1H), 7.20-7.06 (m, 3H), 6.98 (t, J=7.3 Hz, 1H),5.08 (d, J=5.8 Hz, 1H), 4.58 (p, J=6.3 Hz, 1H), 4.30 (d, J=1.7 Hz, 1H),4.22 (d, J=14.0 Hz, 1H), 4.09 (d, J=5.9 Hz, 1H), 3.90-3.76 (m, 4H), 3.70(p, J=8.6 Hz, 1H), 2.53 (s, 1H), 2.42-2.27 (m, 1H), 2.07 (ddq, J=46.2,27.2, 9.8, 9.0 Hz, 4H), 1.81 (t, J=9.5 Hz, 1H), 1.01 (d, J=5.5 Hz, 12H),0.79 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 593.0 (M+H)⁺.

Example 102(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 102A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((R)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example98A, substituting (R)-tetrahydrofuran-2-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid. The crude product was takendirectly into the next step without further purification. MS (ESI⁺) m/z621.4 (M+H)⁺.

Example 102B(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((R)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure of Example98B, substituting Example 102A for Example 98A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.25 (m, 1H), 7.85 (m, 1H), 7.20-7.13 (m, 1H), 7.13-7.04(m, 2H), 6.95 (t, J=7.5 Hz, 1H), 5.39 (d, J=5.8 Hz, 1H), 4.93 (m, 1H),4.44 (m, 1H), 4.31 (d, J=14.0 Hz, 1H), 4.21 (d, J=5.8 Hz, 1H), 3.86 (s,3H), 3.83 (m, 1H), 3.76-3.66 (m, 2H), 3.23 (m, 1H), 2.65 (s, 1H), 1.99(m, 1H), 1.95-1.73 (m, 3H), 1.25 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.8 Hz,3H), 1.05 (s, 9H); MS (ESI⁺) m/z 593.0 (M+H)⁺.

Example 103(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 179 substituting Core 14 for Core 24, using the first elutingdiastereomer as described in Example 179F. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.31 (s, 1H), 8.28 (s, 1H), 7.27 (s, 1H), 7.17 (s, 2H), 7.09 (d,J=2.2 Hz, 1H), 5.80 (s, 1H), 4.63-4.54 (m, 1H), 4.37 (d, J=14.0 Hz, 1H),4.32 (d, J=6.3 Hz, 1H), 4.00 (d, J=14.0 Hz, 1H), 3.88 (s, 3H), 3.80 (d,J=11.2 Hz, 1H), 3.25 (bs, 2H), 2.58 (s, 1H), 1.70 (s, 1H), 1.54 (s, 2H),1.37 (bs, 3H), 1.01 (s, 9H); MS (ESI+) m/z 599 (M+H)⁺.

Example 104(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 179 substituting Core 14 for Core 24 using the second elutingdiastereomer as described in Example 179F. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.27 (s, 1H), 8.18 (s, 1H), 7.20 (d, J=6.4 Hz, 1H), 7.09 (s, 2H),6.98 (s, 1H), 5.41 (s, 1H), 4.70 (s, 1H), 4.38 (d, J=14.2 Hz, 1H), 4.28(d, J=6.5 Hz, 1H), 4.01 (d, J=14.2 Hz, 1H), 3.89 (s, 3H), 3.85 (bs, 1H),2.79 (s, 1H), 3.44 (bs, 2H), 1.81 (s, 1H), 1.61 (s, 1H), 1.51 (d, J=13.9Hz, 1H), 1.46 (s, 3H), 1.01 (s, 9H); MS (ESI+) m/z 599 (M+H)⁺.

Example 105(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]phenyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 73A-73E, Core 15 for Core 6 in Example 73A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.29-8.24 (m, 1H), 7.82 (dd, J=7.6, 1.8 Hz, 1H),7.17-7.11 (m, 1H), 7.09-7.00 (m, 1H), 6.84-6.72 (m, 2H), 5.30 (d, J=5.8Hz, 1H), 4.66 (hept, J=6.2 Hz, 1H), 4.52 (hept, J=6.0 Hz, 1H), 4.40-4.28(m, 2H), 4.22 (dd, J=5.8, 1.5 Hz, 1H), 3.94 (dt, J=13.9, 1.0 Hz, 1H),3.87 (s, 3H), 2.58 (m, 1H), 1.25 (dd, J=10.5, 6.0 Hz, 6H), 1.04 (d,J=6.2 Hz, 3H), 1.01 (s, 9H), 0.90 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 597(M+H)⁺.

Example 106(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 106A (2-methoxyquinolin-3-yl)methanol

2-Methoxyquinoline-3-carbaldehyde (1.45 g, 7.75 mmol) was suspended inmethanol (20 mL) and cooled to 0° C. Sodium borohydride (600 mg, 15.86mmol) was added, causing bubbling. The reaction mixture stirred at 0° C.to room temperature overnight (ice bath melted). The reaction mixturewas concentrated, and the crude material was taken up in saturatedaqueous sodium bicarbonate solution (50 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated to provide the title compound (1.46g, 7.72 mmol, 100% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.19 (q,J=1.2 Hz, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.82-7.72 (m, 1H), 7.62(ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.42 (ddd, J=8.1, 6.9, 1.2 Hz, 1H),5.44-5.30 (m, 1H), 4.66-4.54 (m, 2H), 4.01 (s, 3H); MS (ESI+) m/z 190(M+H)⁺.

Example 106B 3-(bromomethyl)-2-methoxyquinoline

Example 106A (1.46 g, 7.72 mmol) and triphenylphosphine (4.00 g, 15.25mmol) were dissolved in dichloromethane (25 mL) and cooled in an icebath. N-bromosuccinimide (1.373 g, 7.72 mmol) was added gradually usinga solid addition funnel, keeping the internal temperature below 10° C.The ice bath was removed, and after stirring for 15 minutes the reactionwas complete. The reaction was quenched by adding 10 mL of water,stirred for 5 minutes, and the layers were separated. The organics werewashed twice with water, and filtered through a fritted cartridgelayered with a pad of silica (1 cm), eluting with heptanes. Thefiltrates were reduced in volume. The mixture was filtered and washedwith 3×30 mL of 50:50 methyl tert-butyl ether:heptanes, and the solventwas removed in vacuo. The crude material was purified using a 40 gsilica gel cartridge eluting with dichloromethane to provide the titlecompound (1.01 g, 4.01 mmol, 51.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δppm 8.35 (s, 1H), 7.86 (dd, J=8.1, 1.4 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H),7.67 (ddd, J=8.3, 6.9, 1.5 Hz, 1H), 7.44 (ddd, J=8.2, 6.8, 1.2 Hz, 1H),4.74 (s, 2H), 4.05 (s, 3H); MS (ESI+) m/z 252 (M+H)⁺.

Example 106C 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxyquinolin-3-yl)methoxy)-5-phenylpyrrolidine-1,2-dicarboxylate

Example 38C (100.6 mg, 0.267 mmol) and3-(bromomethyl)-2-methoxyquinoline (Example 106B, 112.6 mg, 0.447 mmol)were dissolved in dimethylformamide (1.5 mL). The reaction was cooled to0° C., potassium tert-butoxide (1M in tetrahydrofuran, 0.30 mL, 0.30mmol) was added dropwise, and the reaction was stirred at ambienttemperature for 1 hour. The reaction was quenched by the addition of 1Maqueous HCl (0.1 mL) and purified by silica gel chromatography (5% to100% ethyl acetate in heptanes) to provide the title compound (71.9 mg,49.2%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.67 (dt, J=8.8, 1.0Hz, 1H), 7.63-7.57 (m, 2H), 7.57-7.50 (m, 2H), 7.34 (ddd, J=8.0, 6.9,1.2 Hz, 1H), 7.31 (q, J=1.0 Hz, 1H), 7.26-7.20 (m, 2H), 7.20-7.14 (m,1H), 5.04 (d, J=6.2 Hz, 1H), 4.65 (hept, J=6.2 Hz, 1H), 4.38 (d, J=3.2Hz, 1H), 4.34 (dd, J=13.6, 1.2 Hz, 1H), 4.28 (dd, J=6.2, 2.6 Hz, 1H),4.12 (qd, J=7.1, 0.9 Hz, 2H), 4.02 (dd, J=13.7, 1.3 Hz, 1H), 3.92 (s,3H), 2.50 (t, J=2.9 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 1.06 (d, J=6.2 Hz,3H), 1.01 (s, 9H), 0.91 (d, J=6.3 Hz, 3H); MS (ESI+) m/z 549 (M+H)⁺.

Example 106D(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 106C (62.3 mg, 0.114 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). LiOH (1 M aqueous, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL) and purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound (48.1 mg, 67%) as the TFA salt. ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.70-7.50 (m, 5H), 7.38-7.30 (m, 2H),7.25-7.13 (m, 3H), 5.02 (d, J=6.2 Hz, 1H), 4.65 (hept, J=6.2 Hz, 1H),4.39-4.31 (m, 2H), 4.26 (dd, J=6.2, 2.2 Hz, 1H), 4.01 (dd, J=13.9, 1.3Hz, 1H), 3.92 (s, 3H), 2.53 (t, J=2.6 Hz, 1H), 1.06 (d, J=6.2 Hz, 3H),1.02 (s, 9H), 0.90 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 521 (M+H)⁺.

Example 107(2S,3R,4S,5S)-3-tert-butyl-4-{[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 64 (250 mg, 0.464 mmol) was dissolved in 2 mL of 1,4-dioxane ina 20-mL scintillation vial, and hydrochloric acid (6M in water, 2.0 mL,12 mmol) was added. The vial was capped and heated to 60° C. for 6hours, at which point complete demethylation had occurred as indicatedby LC/MS. The vial was cooled to ambient temperature. The material wasremoved via filtration through a fritted funnel and dried to constantweight in a vacuum oven at 50° C. to provide 197 mg of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.66-7.49 (m, 3H),7.28-6.98 (m, 3H), 6.81 (dt, J=2.9, 1.4 Hz, 1H), 5.00 (d, J=6.2 Hz, 1H),4.64 (hept, J=6.2 Hz, 1H), 4.33 (d, J=3.0 Hz, 1H), 4.24 (dd, J=6.2, 2.2Hz, 1H), 4.15 (dt, J=14.5, 1.0 Hz, 1H), 3.74 (dt, J=14.6, 1.1 Hz, 1H),2.48 (m, J=1.9 Hz, 1H), 1.06 (d, J=6.2 Hz, 3H), 1.02 (s, 9H), 0.89 (d,J=6.2 Hz, 3H); MS (ESI+) m/z 524.9 (M+H)⁺.

Example 108(2S,3R,4S,5S)-3-tert-butyl-5-[2-(3,6-dihydro-2H-pyran-4-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 65 substituting Example 86D for Example 40A, and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor (2-fluoro-4-methylphenyl)boronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.27 (s, 1H), 8.00-7.92 (m, 1H), 7.23 (d,J=2.4 Hz, 1H), 7.20-7.02 (m, 2H), 6.96 (dd, J=7.2, 1.7 Hz, 1H), 5.50 (s,1H), 5.08 (d, J=5.4 Hz, 1H), 4.62 (p, J=6.2 Hz, 1H), 4.38 (d, J=1.6 Hz,1H), 4.34-4.25 (m, 1H), 4.14 (q, J=2.8 Hz, 2H), 3.98 (d, J=5.4 Hz, 1H),3.92-3.68 (m, 6H), 2.43 2.12 (m, 2H), 1.00 (d, J=11.0 Hz, 12H), 0.81 (d,J=6.2 Hz, 3H); MS (APCI+) m/z 621.3 (M+H)⁺.

Example 109(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 109A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-3-carbonyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example98A, substituting (S)-tetrahydrofuran-3-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid. The crude product was takendirectly into the next step without further purification. MS (ESI⁺) m/z621.8 (M+H)⁺.

Example 109B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure of Example98B, substituting Example 109A for Example 98A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.27 (s, 1H), 8.00-7.93 (m, 1H), 7.25-7.06 (m, 3H), 7.02(t, J=7.5 Hz, 1H), 5.45 (d, J=5.8 Hz, 1H), 4.65 (m, 1H), 4.36-4.23 (m,2H), 3.86 (s, 3H), 3.84 (m, 1H), 3.74 (m, 1H), 3.68 (m, 1H), 3.57-3.44(m, 2H), 3.26 (m, 1H), 2.99 (m, 1H), 2.59 (m, 1H), 1.90 (m, 2H), 1.25(m, 3H), 1.16 (d, J=6.7 Hz, 3H), 1.04 (s, 9H); MS (ESI⁺) m/z 593.2(M+H)⁺.

Example 110(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-(oxane-4-carbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 110A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example98A, substituting tetrahydro-2H-pyran-4-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid. The crude product was takendirectly into the next step without further purification. MS (ESI⁺) m/z635.6 (M+H)⁺.

Example 110B(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure of Example98B, substituting Example 110A for Example 98A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.26 (m, 1H), 7.99 (m, 1H), 7.22 (m, 1H), 7.11 (m, 2H),7.00 (m, 1H), 5.42 (d, J=5.9 Hz, 1H), 4.63 (m, 1H), 4.36-4.22 (m, 2H),3.86 (s, 3H), 3.84 (m, 1H), 3.77 (m, 2H), 3.67 (m, 1H), 3.26 (m, 1H),3.10 (m, 1H), 2.83 (m, 1H), 2.58 (m, 1H), 1.53 (m, 4H), 1.27 (d, J=6.8Hz, 3H), 1.16 (d, J=6.8 Hz, 3H), 1.03 (s, 9H); MS (ESI⁺) m/z 607.1(M+H)⁺.

Example 111(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 111A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((R)-tetrahydrofuran-3-carbonyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example98A, substituting (R)-tetrahydrofuran-3-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid. The crude product was takendirectly into the next step without further purification. MS (ESI+) m/z621.7 (M+H)⁺.

Example 111B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure of Example98B, substituting Example 111A for Example 98A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.27 (m, 1H), 7.94 (m, 1H), 7.20-6.98 (m, 4H), 5.42 (d,J=5.9 Hz, 1H), 4.66 (d, J=1.9 Hz, 1H), 4.36-4.22 (m, 2H), 3.86 (s, 3H),3.89-3.75 (m, 2H), 3.66 (m, 1H), 3.53 (m, 2H), 3.24 (h, J=6.9 Hz, 1H),2.99 (m, 1H), 2.61 (m, 1H), 1.88-1.59 (m, 2H), 1.24 (d, J=6.8 Hz, 3H),1.15 (d, J=6.8 Hz, 3H), 1.04 (s, 9H); MS (ESI+) m/z 593.2 (M+H)⁺.

Example 112(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 112A 1-allyl 2-ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

Core 12 (2.00 g, 5.55 mmol) was dissolved in toluene (10 mL) andsaturated aqueous NaHCO₃ (10 mL) was added followed by allylchloroformate (0.708 mL, 6.66 mmol). The reaction was stirred at ambienttemperature for 17 hours, at which point it was complete. The reactionwas diluted with dichloromethane (50 mL) and washed with 1M aqueous HCl(2×50 mL) and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated to provide the crude product. The residue waspurified by silica gel chromatography (5% ethyl acetate indichloromethane) to provide the title compound (1.76 g, 71%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.78 (dd, J=7.6, 1.7 Hz, 1H),7.17-7.04 (m, 2H), 7.01-6.95 (m, 1H), 6.00 (d, J=8.6 Hz, 1H), 5.67 (ddt,J=17.2, 10.4, 5.2 Hz, 1H), 5.56 (dd, J=8.6, 2.5 Hz, 1H), 5.05-4.89 (m,2H), 4.60 (d, J=3.4 Hz, 1H), 4.41 (dq, J=5.2, 1.5 Hz, 2H), 4.27 (qd,J=7.1, 1.0 Hz, 2H), 3.05 (ddd, J=3.3, 2.5, 0.7 Hz, 1H), 2.06 (tt, J=8.5,5.4 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H), 1.04 (s, 9H), 1.02-0.88 (m, 2H),0.85-0.75 (m, 1H), 0.54 (dtd, J=7.9, 5.1, 2.9 Hz, 1H); MS (ESI+) m/z 445(M+H)⁺.

Example 112B 1-allyl 2-ethyl(2S,3R,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 112A (1.79 g, 3.93 mmol) was dissolved in 44 mL of ethanol andthe solution was heated to 75° C. A separate solution of CrCl₂ wasprepared by dissolving pyridinium dichromate (4.066 g, 10.81 mmol) in 88mL of 6M aqueous HCl and adding Zn (7.904 g, 119 mmol) in portions whilecooling in an ice bath. The suspension was stirred until all Zndissolved, leaving a brilliant blue solution. The CrCl₂ solution wastransferred via cannula over 15 minutes to the solution of startingmaterial and heating was continued for 16 hours. The temperature wasmaintained between 70° C. and 75° C. during the addition, and wasmaintained between 75° C. and 80° C. overnight (total 16 hours). Thereaction mixture was cooled to room temperature, diluted with water andextracted with dichloromethane (3×200 mL). The combined extracts werewashed with brine, and dried over sodium sulfate, filtered, andconcentrated. The crude residue was dissolved ethanol (6 mL). A separatesolution of HCl/ethanol was prepared by addition of 1 mL of acetylchloride to 4 mL of ethanol at 0° C., and poured into the reaction flaskand the mixture was heated to 45° C. for 1 hour. The reaction mixturewas concentrated in vacuo and loaded onto a 40 g silica gel column andwas eluted with 5% ethyl acetate in dichloromethane over to provide thetitle compound (518.9 mg, 32%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm7.69 (dd, J=7.1, 2.0 Hz, 1H), 7.19-7.05 (m, 3H), 5.74-5.63 (m, 2H),5.07-4.94 (m, 2H), 4.65 (d, J=5.0 Hz, 1H), 4.45 (dd, J=5.3, 1.8 Hz, 2H),4.28-4.18 (m, 2H), 2.63 (dd, J=5.0, 0.9 Hz, 1H), 2.13 (tt, J=8.5, 5.4Hz, 1H), 1.26 (td, J=7.1, 0.8 Hz, 3H), 1.07 (d, J=0.8 Hz, 9H), 0.95-0.83(m, 2H), 0.83-0.72 (m, 1H), 0.52 (dddd, J=7.8, 6.6, 3.9, 1.5 Hz, 1H); MS(ESI+) m/z 414 (M+H)⁺.

Example 112C 1-allyl 2-ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 112B (504.6 mg, 1.220 mmol) was dissolved in ethanol (5 mL), andthe reaction was cooled to 0° C. Sodium borohydride (75.0 mg, 1.982mmol) was added and the reaction was stirred at 0° C. for 1 hour, andwarmed to ambient temperature for another 1 hour. The solvent wasremoved in vacuo and the residue was extracted with ethyl acetate (50mL), washed with saturated aqueous NaHCO₃ (50 mL) and brine (50 mL),dried over Na₂SO₄, filtered, and concentrated to provide crude product,which was purified by silica gel chromatography (5% ethyl acetate indichloromethane) to provide the title compound (280 mg, 55%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.89-7.83 (m, 1H), 7.10-7.04 (m, 2H),7.01-6.95 (m, 1H), 5.72-5.60 (m, 1H), 5.51 (d, J=6.2 Hz, 1H), 5.03-4.91(m, 2H), 4.45 (td, J=5.6, 2.9 Hz, 1H), 4.36 (td, J=3.5, 2.1 Hz, 3H),4.18 (q, J=7.1 Hz, 2H), 3.71 (s, 1H), 2.31 (t, J=3.4 Hz, 1H), 1.97 (tt,J=7.9, 5.4 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.01 (s, 9H), 0.88 (ttd,J=12.7, 8.9, 5.6 Hz, 2H), 0.73 (dtd, J=9.4, 5.4, 3.6 Hz, 1H), 0.61-0.49(m, 1H); MS (ESI+) m/z 416 (M+H)⁺.

Example 112D 1-allyl 2-ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 112C (275.0 mg, 0.662 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (312.1 mg, 1.156mmol) were dissolved in dimethylformamide (2.6 mL). The reaction wascooled to 0° C., and potassium tert-butoxide (1M in tetrahydrofuran,0.80 mL, 0.80 mmol) was added dropwise. The reaction mixture was stirredat ambient temperature for 1 hour. The reaction mixture was poured intosaturated aqueous NH₄Cl (35 mL), extracted with methyl tert-butyl ether(3×35 mL), and purified by silica gel chromatography (5% ethyl acetatein dichloromethane) to provide the title compound (350.8 mg, 88%). ¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.33-8.25 (m, 1H), 7.88 (dd,J=7.3, 2.1 Hz, 1H), 7.20-7.15 (m, 1H), 7.02 (ddd, J=7.0, 4.5, 1.9 Hz,2H), 6.94 (dd, J=6.9, 2.1 Hz, 1H), 5.73-5.58 (m, 2H), 5.05-4.90 (m, 2H),4.52 (d, J=2.0 Hz, 1H), 4.41-4.37 (m, 2H), 4.37-4.33 (m, 1H), 4.27 (d,J=13.8 Hz, 1H), 4.11 (dtd, J=8.0, 6.9, 1.2 Hz, 2H), 3.87-3.79 (m, 4H),2.52 (t, J=1.3 Hz, 1H), 1.99 (td, J=8.4, 4.2 Hz, 1H), 1.15 (td, J=7.1,0.7 Hz, 3H), 1.05 (s, 9H), 0.96-0.83 (m, 2H), 0.59 (dd, J=5.2, 2.6 Hz,2H); MS (ESI+) m/z 605 (M+H)⁺.

Example 112E ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 112D (350 mg, 0.579 mmol) was dissolved in ethyl acetate (2.5mL) and dichloromethane (2.5 mL) and treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (183.2 mg, 1.173 mmol) andtetrakis(triphenylphosphine)palladium (7.2 mg, 6.23 μmol). The reactionmixture was stirred at ambient temperature. After 1 hour, the reactionmixture was diluted with methyl tert-butyl ether (50 mL) and stirredwith 15 mL of 10% aqueous Na₂CO₃ (50 mL) solution for 30 minutes. Thephases were separated, and the organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography, eluting with 5% to 10% ethyl acetate indichloromethane to provide the title compound (220.4 mg, 73%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.29 (s, 1H), 7.59 (dd, J=7.5, 1.7 Hz,1H), 7.36 (d, J=2.4 Hz, 1H), 7.12-7.00 (m, 2H), 6.95 (dd, J=7.2, 1.7 Hz,1H), 4.65 (d, J=4.4 Hz, 1H), 4.23 (d, J=13.8 Hz, 1H), 4.19-4.08 (m, 3H),3.85 (s, 3H), 3.80 (d, J=13.8 Hz, 1H), 3.66 (d, J=6.4 Hz, 1H), 2.40 (dd,J=6.3, 1.6 Hz, 1H), 1.99 (tt, J=8.5, 5.5 Hz, 1H), 1.21 (t, J=7.1 Hz,3H), 1.01 (s, 10H), 0.90 (dq, J=8.3, 2.1 Hz, 2H), 0.68-0.55 (m, 2H); MS(ESI+) m/z 521 (M+H)⁺.

Example 112F ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

(S)-(−)-tetrahydro-2-furoic acid (44.3 mg, 0.382 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M, 250 μL, 0.50 mmol) wasadded followed by dimethylformamide (25 μL). The reaction mixture wasstirred at room temperature for 3 hours, at which point it wasconcentrated, redissolved in dichloromethane (1 mL), and concentratedagain. The residue was taken up in dichloromethane (3×1 mL) and added toa solution of Example 112E (81.3 mg, 0.156 mmol) and triethylamine (100μL, 0.717 mmol) and dichloromethane (3 mL). The reaction was stirred atambient temperature for 17 hours. After this time, the mixture wasdiluted with dichloromethane (100 mL) and washed twice with saturatedaqueous NaHCO₃ and once with brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated to provide the title compound (79.8mg, 83%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.27 (s, 1H), 7.94(d, J=7.2 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.13-7.00 (m, 2H), 6.99-6.93(m, 1H), 5.92 (s, 1H), 4.77 (s, 1H), 4.38 (d, J=5.7 Hz, 1H), 4.28 (d,J=13.9 Hz, 1H), 4.09 (qd, J=7.0, 1.3 Hz, 2H), 3.89-3.81 (m, 5H), 3.66(dd, J=19.4, 12.3 Hz, 2H), 2.50 (s, 1H), 2.07-1.89 (m, 1H), 1.89-1.56(m, 4H), 1.14 (t, J=7.1 Hz, 3H), 1.05 (s, 9H), 0.91 (tdd, J=8.2, 5.3,3.6 Hz, 2H), 0.71-0.52 (m, 2H); MS (ESI+) m/z 619 (M+H)⁺.

Example 112G(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 112F (73.1 mg, 0.118 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL), concentrated andpurified by silica gel chromatography eluting with ethyl acetate toprovide the title compound (61.5 mg, 88%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 8.27 (s, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.12 (d, J=2.5 Hz,1H), 7.06 (q, J=6.7 Hz, 2H), 6.95 (dd, J=7.1, 2.0 Hz, 1H), 5.93 (d,J=11.0 Hz, 1H), 4.71 (d, J=1.8 Hz, 1H), 4.37 (d, J=5.8 Hz, 1H), 4.31 (d,J=14.0 Hz, 1H), 3.93-3.82 (m, 6H), 3.70 (q, J=6.9 Hz, 1H), 3.61 (d,J=7.3 Hz, 1H), 2.56 (s, 1H), 2.09-1.87 (m, 2H), 1.87-1.72 (m, 1H), 1.63(s, 1H), 1.04 (s, 9H), 0.97-0.77 (m, 2H), 0.71-0.60 (m, 1H), 0.60-0.48(m, 1H); MS (ESI+) m/z 591 (M+H)⁺.

Example 113(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylicacid Example 113A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidine-1,2-dicarboxylateand Example 113B (2R,3S,4S,5R)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidine-1,2-dicarboxylate

The title compound was prepared according to the procedure described inExample 88A-Example 88C, substituting Core 16 for Core 5 in Example 88A.Both diastereomers were isolated. The first eluent was Example 113A.LC/MS (APCI+) m/z 445.40 (M+H)⁺. The second eluent was Example 113B.LC/MS (APCI+) m/z 445.45 (M+H)⁺.

Example 113C(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 88D-Example 88G, substituting Example 113A for Example 88C, and2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.77 (d, J=8.1 Hz, 1H), 8.48 (d, J=4.6 Hz, 1H), 7.55-7.38(m, 2H), 6.99 (d, J=8.6 Hz, 1H), 6.87 (d, J=2.3 Hz, 1H), 5.55 (s, 1H),4.83-4.70 (m, 1H), 4.33 (d, J=13.1 Hz, 1H), 4.15 (d, J=6.0 Hz, 1H), 3.97(d, J=13.1 Hz, 1H), 3.71 (s, 3H), 3.67 (d, J=14.8 Hz, 2H), 3.32 (m, 1H),2.59 (s, 1H), 1.86 (dtd, J=74.6, 13.8, 12.8, 7.3 Hz, 4H), 1.01 (s, 9H);MS (ESI+) m/z 619.2 (M+H)⁺.

Example 114(2S,3R,4R,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 88D-Example 88G, substituting Example 113B for Example 88C, and2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.19 (d, J=8.2 Hz, 1H), 8.63 (s, 1H), 7.69 (s, 1H),7.62-7.54 (m, 2H), 7.16 (d, J=8.6 Hz, 1H), 5.88 (s, 1H), 4.75 (s, 1H),4.55 (d, J=11.6 Hz, 1H), 4.41 (d, J=10.5 Hz, 1H), 4.15 (s, 1H), 3.87 (s,3H), 3.74-3.58 (m, 3H), 2.19 (d, J=10.8 Hz, 1H), 1.77 (d, J=67.9 Hz,4H), 1.00 (s, 9H); MS (ESI+) m/z 619.2 (M+H)⁺.

Example 115(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 144 substituting Core 14 for Core 10 and3-(bromomethyl)-5-trifluromethyl-2-methoxypyridine for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.28 (s, 1H), 8.21 (s, 1H), 7.24 (t, J=4.4 Hz, 1H), 7.15(s, 2H), 7.11-7.00 (m, 1H), 5.64 (s, 1H), 4.61 (s, 1H), 4.37 (d, J=13.9Hz, 2H), 4.01 (d, J=13.9 Hz, 1H), 3.88 (s, 3H), 3.74 (s, 1H), 3.66 (s,1H), 2.63 (s, 1H), 1.93 (q, J=5.5, 4.1 Hz, 1H), 1.87-1.74 (m, 1H), 1.70(s, 1H), 1.02 (s, 9H); MS (APCI+) m/z 585 (M+H)⁺.

Example 116(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 116A 1-allyl 2-ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 96C (458.5 mg, 1.098 mmol) and3-(bromomethyl)-2-methoxyquinoline (Example 106B, 300.1 mg, 1.190 mmol)were dissolved in dimethylformamide (2.5 mL). The reaction was cooled to0° C., and potassium tert-butoxide (1M in tetrahydrofuran, 1.20 mL, 1.20mmol) was added dropwise. The reaction mixture was stirred at ambienttemperature for 1 hour. The reaction mixture was poured into saturatedaqueous NH₄Cl (35 mL), extracted with methyl tert-butyl ether (3×35 mL),and purified by silica gel chromatography (5% ethyl acetate indichloromethane) to provide the title compound (291.2 mg, 45%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.27 (s, 1H), 7.88 (dd, J=7.0, 2.2 Hz,1H), 7.18 (s, 1H), 7.07-6.86 (m, 3H), 5.58 (d, J=5.6 Hz, 1H), 4.64 (p,J=6.2 Hz, 1H), 4.46 (d, J=2.0 Hz, 1H), 4.32 (d, J=5.5 Hz, 1H), 4.27 (d,J=13.9 Hz, 1H), 4.11 (qd, J=7.1, 3.0 Hz, 2H), 3.88-3.80 (m, 4H), 2.50(d, J=1.9 Hz, 1H), 2.01-1.92 (m, 1H), 1.15 (td, J=7.0, 0.8 Hz, 3H), 1.03(d, J=10.3 Hz, 12H), 0.90 (ddd, J=10.8, 8.5, 2.1 Hz, 2H), 0.84 (d, J=6.3Hz, 3H), 0.60 (dd, J=5.5, 2.4 Hz, 2H); MS (ESI+) m/z 589 (M+H)⁺.

Example 116B ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 116A (298 mg, 0.506 mmol) was dissolved in ethyl acetate (2.4mL) and dichloromethane (2.4 mL), and treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (155.6 mg, 0.997 mmol) andtetrakis(triphenylphosphine)palladium (5.9 mg, 5.11 μmol). The reactionmixture was stirred at ambient temperature. After 1 hour, the reactionmixture was diluted with methyl tert-butyl ether (50 mL) and stirredwith 15 mL of 10% aqueous Na₂CO₃ (50 mL) solution for 30 minutes. Thephases were separated, and the organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography 5% to 10% ethyl acetate in dichloromethaneto provide the title compound (186.6 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.68 (t, J=7.9 Hz, 2H), 7.61-7.50 (m, 2H), 7.45 (s, 1H), 7.37-7.30(m, 1H), 7.27-7.17 (m, 2H), 7.10 (td, J=7.5, 1.6 Hz, 1H), 4.41 (d, J=4.4Hz, 1H), 4.28 (d, J=13.7 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.97 (dt,J=4.5, 1.4 Hz, 1H), 3.93-3.85 (m, 5H), 3.65 (d, J=6.5 Hz, 1H), 3.23 (dq,J=13.7, 6.8 Hz, 1H), 1.27-1.16 (m, 9H), 1.00 (d, J=1.0 Hz, 9H); MS(ESI+) m/z 506 (M+H)⁺.

Example 116C ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

(S)-(−)-tetrahydro-2-furoic acid (27.6 mg, 0.238 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M, 180 μL, 0.36 mmol) wasadded followed by dimethylformamide (25 μL). The reaction mixture wasstirred at room temperature for 3 hours, concentrated, redissolved indichloromethane (1 mL), and concentrated again. The residue was taken upin dichloromethane (3×1 mL) and added to a solution of Example 116B(61.7 mg, 0.122 mmol) and triethyl amine (100 μL, 0.717 mmol) indichloromethane (3 mL). The reaction was stirred at ambient temperaturefor 18 hours. The mixture was diluted with dichloromethane (100 mL) andwashed twice with saturated aqueous NaHCO₃ and once with brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated toprovide the title compound (57.0 mg, 77%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 8.04 (d, J=7.9 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.57-7.47(m, 2H), 7.37-7.30 (m, 1H), 7.25 (d, J=6.2 Hz, 2H), 7.14 (d, J=11.3 Hz,2H), 5.68 (s, 1H), 4.76 (s, 1H), 4.39-4.30 (m, 1H), 4.27 (d, J=5.6 Hz,1H), 4.11 (q, J=7.1 Hz, 2H), 3.97-3.88 (m, 5H), 3.73-3.55 (m, 2H), 3.26(p, J=6.7 Hz, 1H), 2.54 (s, 1H), 2.07-1.93 (m, 1H), 1.87-1.56 (m, 3H),1.25 (d, J=6.7 Hz, 3H), 1.17-1.10 (m, 6H), 1.05 (s, 9H), 0.91 (tdd,J=8.2, 5.3, 3.6 Hz, 2H), 0.71-0.52 (m, 2H); MS (ESI+) m/z 603 (M+H)⁺.

Example 116D(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 116C (54.0 mg, 0.090 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL), concentrated, andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (47.6 mg, 77%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.13-8.06 (m, 1H), 7.68-7.63(m, 1H), 7.53 (td, J=8.1, 1.3 Hz, 2H), 7.33 (ddd, J=8.1, 6.9, 1.2 Hz,1H), 7.24 (d, J=7.1 Hz, 2H), 7.17 (s, 1H), 7.11 (t, J=7.3 Hz, 1H), 5.68(s, 1H), 4.73 (d, J=1.8 Hz, 1H), 4.37 (dd, J=14.1, 1.4 Hz, 1H), 4.26 (d,J=5.8 Hz, 1H), 4.20-4.00 (m, 1H), 3.93 (dd, J=14.2, 1.5 Hz, 1H), 3.91(s, 3H), 3.70 (q, J=7.0, 5.5 Hz, 1H), 3.65-3.55 (m, 1H), 3.26 (p, J=6.8Hz, 1H), 2.60 (s, 1H), 2.05-1.93 (m, 1H), 1.87-1.74 (m, 1H), 1.73-1.55(m, 2H), 1.25 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.7 Hz, 3H), 1.04 (s, 9H);MS (ESI+) m/z 575 (M+H)⁺.

Example 117(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 117A (2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

To a cooled (ice bath) solution of (2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(Example 124E, 435 mg, 0.778 mmol) in dichloromethane (5 mL) was addedtriethylamine (0.636 mL, 4.56 mmol) followed by dropwise addition of(S)-tetrahydrofuran-2-carbonyl chloride (220 mg, 1.633 mmol) as asolution in 3 mL dichloromethane. After stirring at room temperature for5 minutes, the reaction was quenched with 10 mL of saturated aqueoussodium bicarbonate. The organic layer was separated, dried with Na₂SO₄,filtered, and concentrated. The resulting crude material waschromatographed using a 24 g silica gel cartridge with a gradient of0-70% ethyl acetate/heptanes to provide the title compound (0.490 g,0.745 mmol, 96% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.36-8.26 (m,1H), 7.85 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.24(d, J=2.3 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 5.50-5.28 (m, 1H), 4.75-4.59(m, 1H), 4.42-4.25 (m, 2H), 4.10 (qq, J=6.5, 3.7 Hz, 2H), 4.00-3.84 (m,4H), 3.77-3.58 (m, 2H), 2.44 (s, 1H), 2.03-1.85 (m, 1H), 1.85-1.73 (m,1H), 1.73-1.58 (m, 1H), 1.16 (td, J=7.1, 0.9 Hz, 3H), 1.01 (s, 9H),0.94-0.74 (m, 2H); MS (APCI+) m/z 659 (M+H)⁺.

Example 117B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(3-(prop-1-en-2-yl)phenyl)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

A mixture of (2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate(Example 117A, 150 mg, 0.228 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (65.2 mg,0.388 mmol) and cesium fluoride (120 mg, 0.787 mmol) in dioxane (2 mL)was degassed for 5 minutes, then1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (11.36 mg, 0.014 mmol) was added. The reactionmixture was purged with nitrogen and heated to 100° C. for 2 hours. Thereaction mixture was cooled to room temperature before dichloromethane(10 mL) was added. The resulting mixture was filtered over a pad ofsilica gel, washed with 35% ethyl acetate in heptanes solution (10 mL),and concentrated. Purification of the residue via chromatography on a 12g silica gel cartridge eluting with 0 to 30% ethyl acetate in heptanesprovided the title compound (125 mg, 89% yield). LC/MS (APCI+) m/z619.58 (M+H)⁺.

Example 117C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

Example 117B (120 mg, 0.194 mmol) in ethanol (1.2 mL) was added to 5%Pt/C (75 mg, 0.158 mmol) in a 20 mL pressure bottle. The mixture wasstirred under 50 psi of hydrogen at ambient temperature for 75 minutes.LC/MS indicated the reaction was complete. The mixture was diluted withethanol and filtered through a polypropylene membrane and filtered againthrough a diatomaceous earth column. The filtrate was concentrated. Theresidue (100 mg, 84%) was used in the next step without furtherpurification. LC/MS (APCI+) m/z 621.9 (M+H)⁺.

Example 117D(2S,3R,4S,5S)-3-(tert-butyl)-5-(3-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylicacid

The mixture of Example 117C (100 mg, 0.161 mmol) in methanol (2 mL) and6M aqueous LiOH (0.5 mL) was stirred at 50° C. for overnight, adjustedpH to 1˜2 by adding 2M aqueous HCl and was concentrated. The residue waspurified by silica gel chromatography, eluting with methanol indichloromethane at 0-20% gradient to provide the title compound, 80 mg(84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.28 (s, 1H), 7.59 (s, 1H),7.44 (d, J=7.7 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H),7.00 (d, J=7.8 Hz, 1H), 5.37 (s, 1H), 4.57 (s, 1H), 4.32-4.25 (m, 2H),4.20 (s, 1H), 3.90 (d, J=7.6 Hz, 1H), 3.87 (s, 3H), 3.74 (q, J=7.2 Hz,1H), 3.63 (s, 1H), 1.70 (d, J=77.7 Hz, 4H), 1.25 (s, 1H), 1.10 (d, J=6.9Hz, 6H), 1.00 (s, 9H); MS (ESI+) m/z 593 (M+H)⁺.

Example 118(2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 117A (54.0 mg, 0.082 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL), concentrated, andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (51.7 mg, 85%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.30 (d, J=2.3 Hz, 1H), 7.89(s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.22 (s, 1H),7.15 (q, J=8.8, 7.8 Hz, 1H), 5.38 (s, 1H), 4.61 (s, 1H), 4.38-4.28 (m,2H), 4.19 (s, 1H), 3.96 (d, J=13.8 Hz, 1H), 3.89 (d, J=0.9 Hz, 3H),3.80-3.58 (m, 2H), 2.51-2.48 (m, 1H), 1.97-1.60 (m, 4H), 1.00 (d, J=0.9Hz, 9H); MS (ESI+) m/z 629 & 631 (M+H)⁺.

Example 119(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 144 substituting Core 8 for Core 10 and3-(bromomethyl)-5-trifluromethyl-2-methoxypyridine for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.30 (s, 1H), 7.76 (s, 1H), 7.57 (d, J=7.5 Hz, 1H),7.27-7.11 (m, 3H), 5.38 (s, 1H), 4.61 (s, 1H), 4.38-4.27 (m, 2H), 4.14(bs, 1H), 3.97 (d, J=13.8 Hz, 1H), 3.89 (s, 3H), 3.74 (q, J=7.2 Hz, 1H),3.65 (m, 1H), 2.49 (s, 1H), 1.89 (s, 1H), 1.80 (dt, J=13.5, 6.6 Hz, 1H),1.67 (s, 1H), 1.01 (s, 9H); MS (APCI+) m/z 585 (M+H)⁺.

Example 120(2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 120A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(3-cyclopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

Example 117A (172.3 mg, 0.262 mmol), cyclopropylboronic acid (38.2 mg,0.445 mmol) and cesium fluoride (137.5 mg, 0.905 mmol) were dissolved indioxane (2 mL). The reaction was degassed for 5 minutes, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (13.0 mg, 0.016 mmol) was added. The reactionmixture was purged with nitrogen and heated to 100° C. The reactionmixture was filtered and purified by reverse-phase preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). Agradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B)was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0minutes linear gradient 95-10% A) to provide the title compound (51.7mg, 85%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.29 (d, J=2.3 Hz,1H), 7.43-7.31 (m, 2H), 7.22 (d, J=2.4 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H),6.90 (d, J=7.7 Hz, 1H), 5.35 (s, 1H), 4.62 (s, 1H), 4.32-4.23 (m, 2H),4.19-4.03 (m, 3H), 3.91-3.80 (m, 5H), 3.71 (q, J=7.1 Hz, 1H), 3.63 (t,J=6.7 Hz, 1H), 2.43 (d, J=2.8 Hz, 1H), 1.90-1.71 (m, 3H), 1.62 (s, 1H),1.15 (td, J=7.1, 0.8 Hz, 3H), 1.00 (s, 9H), 0.88-0.76 (m, 2H), 0.59-0.44(m, 2H); MS (ESI+) m/z 619 (M+H)⁺.

Example 120B(2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 120A (114.4 mg, 0.185 mmol) was dissolved in methanol (1 mL),and tetrahydrofuran (1 mL). Aqueous LiOH (1 M, 1.0 mL, 1.0 mmol) wasadded and the reaction was heated to 50° C. for 16 hours. The reactionwas quenched by the addition of 1M aqueous HCl (1 mL), concentrated, andpurified by silica gel chromatography (ethyl acetate) to provide thetitle compound (90.3 mg, 88%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm8.32-8.24 (m, 1H), 7.38 (d, J=8.9 Hz, 2H), 7.22-7.14 (m, 1H), 7.07 (t,J=7.5 Hz, 1H), 6.91 (d, J=7.6 Hz, 1H), 5.35 (s, 1H), 4.57 (s, 1H),4.35-4.24 (m, 2H), 4.18 (s, 1H), 3.94-3.84 (m, 5H), 3.73 (q, J=7.2 Hz,1H), 3.64 (t, J=6.8 Hz, 1H), 2.49-2.48 (m, 1H), 1.90-1.54 (m, 4H), 1.00(s, 9H), 0.82 (ddd, J=8.4, 4.2, 2.8 Hz, 2H), 0.54 (ddt, J=6.2, 5.1, 1.4Hz, 2H); MS (ESI+) m/z 591 (M+H)⁺.

Example 121(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 121A (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-nitropyrrolidine-1,2-dicarboxylate

To Core 18 (1.5 g, 3.98 mmol) in toluene (10 mL) and saturated aqueousNaHCO₃ (10 mL) was added allyl carbonochloridate (1.059 mL, 9.96 mmol)dropwise at room temperature. The mixture was stirred at roomtemperature for 2 hours. Ethyl acetate (20 mL) was added and the organiclayer was washed with brine and concentrated. Purification of theresidue by chromatography on a 24 g silica gel cartridge eluting withethyl acetate in heptane at 0-40% gradient provided(2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-nitropyrrolidine-1,2-dicarboxylate,(1.2 g, 2.61 mmol, 65.4% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.52 (s,1H), 7.37 (dt, J=7.4, 1.7 Hz, 1H), 7.32-7.29 (m, 1H), 7.26 (q, J=7.6,7.0 Hz, 1H), 5.60 (s, 1H), 5.42 (d, J=8.6 Hz, 1H), 5.29 (dd, J=8.7, 2.4Hz, 1H), 4.98 (s, 1H), 4.71 (s, 1H), 4.58 (d, J=10.2 Hz, 1H), 4.43-4.33(m, 2H), 3.11 (t, J=2.7 Hz, 1H), 1.39 (t, J=7.1 Hz, 3H), 1.33 (s, 9H),1.10 (s, 9H); LC/MS (APCI+) m/z 461.5 (M+H)⁺.

Example 121B (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-oxopyrrolidine-1,2-dicarboxylate

To potassium dichromate (4.22 g, 14.33 mmol) in 6M aqueous HCl (60 mL)was added zinc (4.68 g, 71.7 mmol) portionwise under N₂ atmosphere.After the complete dissolution of zinc yielded a clear light bluesolution, the formed chromium(II) chloride was transferred to therefluxing solution of Example 121A (1.1 g, 2.388 mmol) in ethanol (60mL) under N₂. The reaction mixture was refluxed for 16 hours. Themixture was cooled and concentrated to half of its volume, and extractedwith dichloromethane (60 mL×3). The organic phase was washed withsaturated aqueous NaHCO₃ solution and brine, dried over MgSO₄, filtered,and concentrated. To the residue in ethanol (5 mL) was added preparedacetyl chloride (1.5 mL) in ethanol (5 mL). The mixture was heated at60° C. for 1 hour and the solvent was removed. The residue was dissolvedin dichloromethane (30 mL), washed with brine, dried over MgSO₄,filtered, and concentrated. Purification by chromatography, eluting withmethanol/ethyl acetate (1:9) in heptanes at 0-40% gradient provided thetitle compound 635 mg, (61.9% yield). ¹H NMR (501 MHz, CDCl₃) δ ppm 7.62(s, 1H), 7.40 (dt, J=7.0, 1.8 Hz, 1H), 7.35-7.29 (m, 2H), 5.66 (s, 2H),5.00 (s, 1H), 4.91 (s, 1H), 4.79-4.74 (m, 1H), 4.61 (d, J=13.6 Hz, 1H),4.50 (s, 1H), 4.34-4.24 (m, 2H), 2.59 (dd, J=4.6, 1.1 Hz, 1H), 1.35 (s,9H), 1.32 (d, J=7.2 Hz, 3H), 1.14 (s, 9H); MS (ESI+) m/z 430 (M+H)⁺.

Example 121C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-hydroxypyrrolidine-1,2-dicarboxylateand Example 121D (2S,3R,4R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

To Example 121B (630 mg, 1.467 mmol) in ethanol (10 mL) cooled in anice-bath was added sodium borohydride (83 mg, 2.200 mmol) portionwise.The mixture was stirred in an ice-bath for 30 minutes, and was allowedto warm to ambient temperature. LC/MS showed two product peaks; theratio was about 4/1. The solvent was removed and dichloromethane wasadded. The organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The crude material was purified via chromatography,eluting with ethyl acetate/methanol (9:1) in heptane. The first eluentwas title compound Example 121C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate(422 mg, 66.7% yield); ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.60 (s, 1H),7.38 (dt, J=6.9, 1.7 Hz, 1H), 7.27-7.13 (m, 2H), 5.55 (s, 1H), 4.84 (s,1H), 4.63 (d, J=4.4 Hz, 1H), 4.47-4.38 (m, 1H), 4.32 (d, J=5.9 Hz, 1H),4.24 (s, 1H), 4.16 (q, J=7.1 Hz, 2H), 2.20 (t, J=5.1 Hz, 1H), 1.29 (s,9H), 1.23 (t, J=7.1 Hz, 3H), 0.98 (s, 9H); MS (ESI+) m/z 432 (M+H)⁺. Thesecond eluent was Example 121D (2S,3R,4R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate(105 mg, 16.59% yield) ¹H NMR (501 MHz, DMSO-d₆) δ ppm 7.64 (d, J=24.0Hz, 1H), 7.35 (tt, J=7.9, 2.9 Hz, 1H), 7.23 (dd, J=5.0, 1.4 Hz, 1H),7.22-7.13 (m, 1H), 5.54 (t, J=4.7 Hz, 1H), 5.30-5.14 (m, 1H), 4.95-4.80(m, 1H), 4.75 (d, J=6.3 Hz, 1H), 4.45 (tdd, J=9.4, 6.6, 4.7 Hz, 1H),4.39-4.31 (m, 1H), 4.23-4.03 (m, 3H), 3.99 (dt, J=10.6, 3.8 Hz, 1H),1.93 (ddd, J=17.0, 11.2, 3.3 Hz, 1H), 1.28-1.25 (m, 9H), 1.25-1.17 (m,3H), 0.96 (s, 9H); ); MS (ESI+) m/z 432 (M+H)⁺.

Example 121E (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

To Example 121C (410 mg, 0.950 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (308 mg, 1.140mmol) in dimethylformamide (4 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (139 mg, 1.235 mmol, 1.3 mL, 1.0M intetrahydrofuran) was added dropwise. The mixture was stirred in anice-bath for 30 minutes, and was allowed to warm to room temperature.Saturated NH₄Cl was added. The organic layer washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified viachromatography, eluting with ethyl acetate in heptanes at 0-40% gradientto provide (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate(495 mg, 84% yield). LC/MS (APCI+) m/z 621.3 (M+H)⁺.

Example 121F (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

To a solution of Example 121E (495 mg, 0.797 mmol) in acetonitrile/water(6.6 mL, 10:1) was added diethylamine (0.165 mL, 1.595 mmol) andtetrakis(triphenylphosphine)palladium(0) (20.27 mg, 0.018 mmol). Themixture was stirred at ambient temperature overnight; LC/MS showedconversion was finished. Dichloromethane (30 mL) and water (20 mL) wereadded and the organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. Purification of the residue via silica gelchromatography, eluting with ethyl acetate/methanol (10:1) in heptanesat 0-50% gradient provided the title compound (320 mg, 74.8% yield).LC/MS (APCI+) m/z 537.57 (M+H)⁺.

Example 121G(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

To (S)-tetrahydrofuran-2-carboxylic acid (34.6 mg, 0.298 mmol) and adrop of dimethylformamide in dichloromethane (4 mL) was added oxalyldichloride (56.8 mg, 0.447 mmol, 2.2 mL, 2 M in dichloromethane). Themixture was stirred at room temperature for 30 minutes. The solvent wasremoved under pressure and fresh dichloromethane was added and reactionmixture was concentrated again. The residue was dissolved indichloromethane (1 mL) and added dropwise to a solution of Example 121F(80 mg, 0.149 mmol) and triethylamine (0.083 mL, 0.596 mmol) indichloromethane (4 mL) in an ice-bath. The mixture was stirred at 0° C.for 30 minutes, and allowed to warm to room temperature. Dichloromethaneand saturated aqueous NH₄Cl were added and the organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas dissolved in methanol (1.5 mL) and 6M aqueous LiOH (0.5 mL), and wasstirred at 50° C. for 6 hours. The pH was adjusted to 1˜2 by adding 2Maqueous HCl. The reaction mixture was concentrated, taken up indichloromethane and filtered through a syringe filter. The filtrate waspurified via chromatography, eluting with methanol in dichloromethane ona 12 g silica gel cartridge at 0-20% gradient to provide the titlecompound (65 mg, 0.107 mmol, 71.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 8.28 (s, 1H), 7.79 (s, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.13 (dd,J=16.1, 7.7 Hz, 3H), 5.39 (s, 1H), 4.57 (s, 1H), 4.30 (dd, J=6.5, 2.6Hz, 1H), 4.25 (d, J=13.7 Hz, 1H), 4.19 (s, 1H), 3.86 (d, J=0.7 Hz, 3H),3.74 (q, J=7.2 Hz, 1H), 3.62 (d, J=5.8 Hz, 1H), 2.57 (m, 1H), 1.76 (dd,J=12.1, 6.4 Hz, 2H), 1.59 (s, 1H), 1.25 (m, 1H), 1.18 (d, J=0.7 Hz, 9H),1.01 (s, 9H); MS (ESI+) m/z 607.1 (M+H)⁺.

Example 122(2S,3R,4R,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure describedfrom Example 121C to 121 G, substituting Example 121D for Example 121C.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (s, 1H), 7.99-7.87 (m, 2H), 7.36(d, J=5.1 Hz, 1H), 7.27 (d, J=4.3 Hz, 2H), 5.39 (s, 1H), 4.83 (d, J=12.5Hz, 1H), 4.64 (d, J=12.5 Hz, 1H), 4.38 (d, J=11.0 Hz, 1H), 4.17 (d,J=11.3 Hz, 1H), 3.70 (t, J=7.1 Hz, 1H), 3.62 (dd, J=9.5, 4.0 Hz, 1H),2.19 (dd, J=11.0, 3.7 Hz, 1H), 1.87-1.75 (m, 2H), 1.63 (s, 1H), 1.45 (s,1H), 1.29 (s, 9H), 1.27-0.99 (m, 4H), 0.97 (s, 9H); MS (ESI+) m/z 607.2(M+H)⁺.

Example 123(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 179 substituting Core 8 for Core 24. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.30 (s, 1H), 7.82 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.23 (d, J=2.5Hz, 1H), 7.21-7.12 (m, 2H), 5.39 (s, 1H), 4.51 (d, J=2.8 Hz, 1H), 4.32(d, J=13.9 Hz, 1H), 4.27 (d, J=6.4 Hz, 1H), 3.95 (d, J=13.9 Hz, 1H),3.89 (s, 3H), 3.80 (d, J=11.5 Hz, 1H), 2.62 (s, 1H), 1.68 (s, 1H), 1.52(d, J=10.6 Hz, 1H), 1.46-1.30 (m, 2H), 0.99 (s, 9H); MS (ESI+) m/z 600(M+H)⁺.

Example 124(2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 124A (2S,3R,4S,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-1,2-dicarboxylate

To Core 17 (1.974 g, 4.94 mmol) in toluene (24 mL) and saturated aqueousNaHCO₃ (24 mL) was added allyl carbonochloridate (0.788 mL, 7.42 mmol)dropwise at ambient temperature. The mixture was stirred at ambienttemperature for 30 minutes. Methyl tert-butyl ether (100 mL) was addedand the organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated. The crude material was purified using an 80 gsilica gel cartridge with a gradient of 5-100% ethyl acetate/heptanesover 40 minutes to provide (2S,3R,4S,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-1,2-dicarboxylate(2.263 g, 4.68 mmol, 95% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.78(t, J=1.9 Hz, 1H), 7.51 (ddt, J=7.7, 1.6, 0.8 Hz, 1H), 7.39 (ddd, J=8.0,2.2, 1.1 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 5.73 (ddt, J=16.4, 11.2, 5.2Hz, 1H), 5.66 (dd, J=8.7, 2.9 Hz, 1H), 5.49 (d, J=8.7 Hz, 1H), 5.08 (dt,J=1.7, 1.1 Hz, 1H), 5.05 (dq, J=8.0, 1.6 Hz, 1H), 4.56 (d, J=3.5 Hz,1H), 4.46 (dt, J=5.2, 1.6 Hz, 2H), 4.26 (qd, J=7.1, 0.7 Hz, 2H),2.99-2.93 (m, 1H), 1.30 (t, J=7.1 Hz, 3H), 1.01 (s, 9H); MS (APCI+) m/z483 (M+H)⁺.

Example 124B (2S,3R,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-oxopyrrolidine-1,2-dicarboxylate

To potassium dichromate (8.25 g, 28.1 mmol) in 6 N aqueous HCl (80 mL)was added zinc (10.70 g, 164 mmol) under N₂ atmosphere. After the almostcomplete dissolution of the zinc yielded a clear bright blue solution,the formed chromium(II) chloride was transferred to a refluxing solutionof Example 124A (2.26 g, 4.68 mmol) in ethanol (50 mL) under N₂ using anaddition funnel over 1 hour. The reaction mixture was refluxed at 90° C.overnight, cooled and diluted with 600 mL of dichloromethane. Theorganic phase was and dried over sodium sulfate, filtered andconcentrated. The crude material was then taken up in anhydrous ethanoland treated with a solution of HCl in ethanol (prepared by adding 2.5 mLof acetyl chloride to an ice bath cooled solution of 6 mL of ethanol),and the mixture was heated at 65° C. for one hour. The ethanol wasremoved and the crude material was diluted with 300 mL of methyltert-butyl ether, washed with 50 mL each of saturated aqueous sodiumbicarbonate and brine, dried over sodium sulfate, and filtered. Thesolvent was removed in vacuo to provide (2S,3R,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-oxopyrrolidine-1,2-dicarboxylate(2.04 g, 3.61 mmol, 77% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.70 (t,J=1.9 Hz, 1H), 7.48 (ddd, J=6.9, 1.7, 0.8 Hz, 1H), 7.43 (ddd, J=7.9,2.0, 1.0 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 5.82-5.70 (m, 1H), 5.11 (dt,J=4.7, 1.6 Hz, 1H), 5.09-5.01 (m, 2H), 4.67 (d, J=4.2 Hz, 1H), 4.54-4.48(m, 2H), 4.24-4.16 (m, 2H), 2.59 (dd, J=4.3, 1.1 Hz, 1H), 1.23 (dd,J=7.4, 6.8 Hz, 3H), 1.05 (s, 9H); MS (APCI+) m/z 452 (M+H)⁺.

Example 124C (2S,3R,4S,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 124B (2.04 g, 4.51 mmol) was dissolved in ethanol (20 mL) andcooled in an ice bath. Sodium tetrahydroborate (0.205 g, 5.41 mmol) wasadded initially in small portions but then all at once. The mixture wasallowed to stir in the bath for 30 minutes. The mixture was concentratedin vacuo. Methyl tert-butyl ether (300 mL) and saturated sodiumbicarbonate (50 mL) were added and the mixture was stirred for 30minutes at room temperature. The layers were separated, and the organiclayer was washed with brine, dried over sodium sulfate, filtered, andconcentrated. The resulting residue was loaded onto an 80 g silica gelcolumn and was eluted with 5-50% ethyl acetate/heptanes to provide(2S,3R,4S,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylate(1.062 g, 2.337 mmol, 51.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.75(t, J=1.9 Hz, 1H), 7.49 (ddd, J=7.6, 2.0, 1.1 Hz, 1H), 7.32 (ddd, J=7.9,2.0, 1.0 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 5.71 (ddt, J=17.7, 10.2, 5.1Hz, 1H), 5.10-5.00 (m, 2H), 4.87 (d, J=6.6 Hz, 1H), 4.43-4.38 (m, 2H),4.38-4.31 (m, 1H), 4.28 (d, J=4.6 Hz, 1H), 4.26-4.21 (m, 1H), 4.17 (q,J=7.1 Hz, 2H), 2.24 (t, J=4.4 Hz, 1H), 1.25 (td, J=7.2, 0.7 Hz, 3H),0.99 (d, J=0.7 Hz, 9H); MS (APCI+) m/z 455 (M+H)⁺ Br doublet.

Example 124D (2S,3R,4S,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 124C (788 mg, 1.734 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (940 mg, 3.48mmol) were dissolved in dry dimethylformamide (6 mL). After cooling inan ice bath, 1 M potassium 2-methylpropan-2-olate (2.5 mL, 2.500 mmol)solution in tetrahydrofuran was added dropwise over 15 minutes. After 30minutes, the reaction was acidified with 1M aqueous HCl (0.5 mL) andwarmed to room temperature. The reaction mixture was diluted with 100 mLof methyl tert-butyl ether and washed with water (25 mL). The organicswere separated and dried over sodium sulfate, filtered, andconcentrated. The crude material was purified using a 40 g silica gelcolumn and was eluted with 5-50% ethyl acetate/heptanes over 40 minutesto provide (2S,3R,4S,5S)-1-allyl 2-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate(0.593 g, 0.922 mmol, 53.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31(s, 1H), 7.80 (d, J=1.9 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.30-7.26 (m,1H), 7.24 (d, J=2.4 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 5.71 (ddd, J=18.4,10.3, 5.1 Hz, 1H), 5.09-5.01 (m, 3H), 4.43 (dd, J=3.9, 2.1 Hz, 3H),4.34-4.27 (m, 3H), 4.11 (qd, J=7.1, 2.5 Hz, 2H), 3.93 (d, J=13.5 Hz,1H), 3.88 (s, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.01 (s, 9H); MS (APCI+) m/z643 (M+H)⁺.

Example 124E (2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 124D (160 mg, 0.249 mmol) was dissolved in ethyl acetate (2.5mL) and dichloromethane (2.5 mL), degassed with a stream of nitrogen,and treated with 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (78 mg,0.497 mmol) and tetrakis(triphenylphosphine)palladium (2.87 mg, 2.486mol). The reaction was stirred at ambient temperature for 10 minutes.The reaction mixture was quenched with 15 mL of 2M aqueous Na₂CO₃ andwas diluted with 50 mL of methyl tert-butyl ether. The phases wereseparated, and the organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude material was purifiedusing a 24 g silica gel cartridge with a gradient of 5-100% ethylacetate/heptanes over 20 minutes to provide (2S,3R,4S,5S)-ethyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(103 mg, 0.184 mmol, 74.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.32(s, 1H), 7.67 (t, J=1.9 Hz, 1H), 7.46-7.37 (m, 2H), 7.31 (ddd, J=7.9,2.1, 1.1 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 4.30 (dt, J=13.6, 0.8 Hz, 1H),4.22 (d, J=4.9 Hz, 1H), 4.17-4.06 (m, 3H), 3.93 (dt, J=13.6, 0.9 Hz,1H), 3.88 (s, 3H), 3.66 (d, J=6.1 Hz, 1H), 3.01 (s, 1H), 2.40 (dd,J=6.1, 2.2 Hz, 1H), 1.20 (t, J=7.1 Hz, 3H), 0.98 (s, 9H); (APCI+) m/z559 (M+H)⁺.

Example 124F (2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

To a solution of Example 124E (75 mg, 0.134 mmol) in toluene (1 mL) andsaturated aqueous NaHCO₃ (1.000 mL) was added dropwise 2M isopropylcarbonochloridate (0.141 mL, 0.282 mmol) as a solution in toluene. Afterstirring at room temperature for 20 minutes, LC/MS showed desiredproduct with no starting material left. The organics were concentratedand chromatographed using an 12 g silica gel cartridge with a gradientof 5-100% ethyl acetate/heptanes to provide (2S,3R,4S,5S)-2-ethyl1-isopropyl5-(3-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate(59 mg, 0.091 mmol, 68.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31(d, J=2.4 Hz, 1H), 7.79 (t, J=1.8 Hz, 1H), 7.52 (dt, J=7.7, 1.3 Hz, 1H),7.31-7.23 (m, 2H), 7.12 (t, J=7.8 Hz, 1H), 5.01 (d, J=6.0 Hz, 1H), 4.66(p, J=6.2 Hz, 1H), 4.37 (d, J=2.9 Hz, 1H), 4.33-4.27 (m, 2H), 4.11 (qd,J=7.1, 4.9 Hz, 2H), 3.93 (dt, J=13.6, 0.9 Hz, 1H), 3.88 (s, 3H),2.45-2.42 (m, 1H), 1.17 (t, J=7.1 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.01(s, 9H), 0.93 (d, J=6.3 Hz, 3H); MS (APCI+) m/z 645 (M+H)⁺.

Example 124G(2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 124F (58 mg, 0.090 mmol) and lithium hydroxide (20.4 mg, 0.852mmol) were dissolved in methanol (0.5 mL), tetrahydrofuran (0.500 mL)and water (0.500 mL). The reaction mixture was warmed at 45° C.overnight. The solvent was removed under a stream of nitrogen and wasacidified with 0.422 mL of 2N aqueous HCl. The crude material waschromatographed using a 12 g silica gel cartridge with an ethanol/ethylacetate/heptanes solvent system to provide(2S,3R,4S,5S)-5-(3-bromophenyl)-3-(tert-butyl)-1-(isopropoxycarbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylicacid (32 mg, 0.052 mmol, 57.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.32-8.27 (m, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.66-7.60 (m, 1H), 7.29-7.22(m, 1H), 7.22-7.17 (m, 1H), 7.09 (t, J=7.8 Hz, 1H), 4.99 (d, J=6.4 Hz,1H), 4.64 (p, J=6.2 Hz, 1H), 4.32 (d, J=13.9 Hz, 1H), 4.28-4.22 (m, 2H),4.00-3.93 (m, 1H), 3.89 (s, 3H), 2.52 (t, J=2.7 Hz, 1H), 1.06 (d, J=6.2Hz, 3H), 0.99 (s, 9H), 0.91 (d, J=6.2 Hz, 3H); MS (APCI+) m/z 617(M+H)⁺.

Example 125(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 179 substituting Core 8 for Core 24. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.30 (s, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.25-7.04 (m, 3H), 5.18(s, 1H), 4.81 (s, 1H), 4.33 (d, J=13.9 Hz, 1H), 4.29-4.23 (m, 1H), 3.96(d, J=13.9 Hz, 2H), 3.89 (d, J=0.7 Hz, 3H), 3.81 (s, 1H), 2.60 (s, 1H),1.78 (s, 1H), 1.54 (s, 2H), 1.43 (s, 3H), 1.01 (s, 9H); MS (ESI+) m/z600 (M+H)⁺.

Example 126(2S,3R,4R,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 126A 1-allyl 2-ethyl(2S,3R,4R,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 144B (633 mg, 1.399 mmol) was dissolved in ethanol (10 mL).Sodium borohydride (52.9 mg, 1.399 mmol) was added after cooling thereaction to ˜−10° C. in an ice-acetone bath. The ice bath was removedand the reaction was allowed to warm to room temperature, which tookabout 20 minutes, at which point LC/MS showed the starting material wascompletely consumed. The reaction mixture was concentrated and stirredin ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL) for 30minutes. The organics were concentrated and purified by silica gelchromatography, eluting with 0 to 5% ethyl acetate in dichloromethane toprovide the desired product (101.5 mg, 16%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 8.10 (dd, J=7.8, 1.7 Hz, 1H), 7.57 (dd, J=7.9, 1.2 Hz,1H), 7.34 (td, J=7.6, 1.3 Hz, 1H), 7.17 (td, J=7.6, 1.7 Hz, 1H), 5.76(s, 1H), 5.24 (d, J=5.8 Hz, 1H), 5.08 (d, J=10.6 Hz, 2H), 4.98 (s, 1H),4.48-4.39 (m, 3H), 4.28-4.08 (m, 3H), 2.01-1.86 (m, 1H), 1.29 (t, J=7.1Hz, 3H), 0.97 (s, 9H); MS (ESI+) m/z 454 (M+H)⁺.

Example 126B 1-allyl 2-ethyl(2S,3R,4R,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 126A (92.2 mg, 0.203 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (123.8 mg, 0.458mmol) were dissolved in dimethylformamide (1 mL). The reaction mixturewas cooled to 0° C., potassium tert-butoxide (1M in tetrahydrofuran,0.30 mL, 0.30 mmol) was added dropwise and the reaction was stirred atambient temperature for 1 hour. The reaction mixture was poured intosaturated aqueous NH₄Cl (35 mL), extracted with methyl tert-butyl ether(3×35 mL), and purified by silica gel chromatography (5% ethyl acetatein dichloromethane) to provide the title compound (57.1 mg, 44%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.46 (d, J=2.1 Hz, 1H), 8.25 (dd,J=7.9, 1.8 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.60 (dd, J=7.9, 1.3 Hz,1H), 7.39 (td, J=7.6, 1.3 Hz, 1H), 7.23 (td, J=7.6, 1.7 Hz, 1H),5.80-5.67 (m, 1H), 5.28 (s, 1H), 5.07 (t, J=10.9 Hz, 2H), 4.72 (d,J=12.6 Hz, 1H), 4.46-4.39 (m, 3H), 4.31-4.12 (m, 3H), 4.08 (d, J=3.5 Hz,1H), 3.98 (s, 3H), 2.21 (dd, J=11.1, 3.4 Hz, 1H), 1.29 (t, J=7.1 Hz,3H), 0.95 (s, 9H); MS (ESI+) m/z 643 & 645 (M+H)⁺.

Example 126C ethyl(2S,3R,4R,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 126B (54.0 mg, 0.084 mmol) was dissolved in ethyl acetate (1 mL)and dichloromethane (1 mL) and was treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (26.2 mg, 0.168 mmol) andtetrakis(triphenylphosphine)palladium (1.0 mg, 0.865 μmol). The reactionwas stirred at ambient temperature. After 1 hour, the reaction mixturewas diluted with methyl tert-butyl ether (25 mL) and stirred with 15 mLof 10% aqueous Na₂CO₃ (50 mL) solution for 30 minutes. The phases wereseparated, and the organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel chromatography, eluting with 5% to 10% ethyl acetate indichloromethane to provide the title compound (47.0 mg, 100%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.54 (dd, J=2.6, 1.2 Hz, 1H), 8.36 (dd, J=7.9,1.8 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.54 (dd, J=8.0, 1.3 Hz, 1H), 7.39(td, J=7.4, 1.2 Hz, 1H), 7.18 (td, J=7.6, 1.8 Hz, 1H), 5.07 (d, J=12.8Hz, 1H), 5.04 (d, J=1.1 Hz, 1H), 4.66-4.59 (m, 2H), 4.14 (qq, J=7.2, 3.8Hz, 2H), 4.06-3.98 (m, 1H), 3.97 (s, 3H), 3.91 (d, J=3.5 Hz, 1H), 2.04(dd, J=10.3, 3.5 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.88 (s, 9H); MS(ESI+) m/z 559 & 561 (M+H)⁺.

Example 126D ethyl(2S,3R,4R,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

(S)-(−)-tetrahydro-2-furoic acid (40.2 mg, 0.345 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M in dichloromethane, 200 μL,0.40 mmol) was added followed by dimethylformamide (25 μL). The reactionmixture was stirred at room temperature for 3 hours, at which point itwas concentrated, redissolved in dichloromethane (1 mL), andconcentrated again. The residue was taken up in dichloromethane (3×1 mL)and was added to a solution of Example 126C (47.0 mg, 0.084 mmol) andtriethylamine (100 μL, 0.717 mmol) and dichloromethane (3 mL). Thereaction mixture was stirred at ambient temperature for 17 hours. Afterthis time, the mixture was diluted with dichloromethane (50 mL) andwashed twice with saturated NaHCO₃ and once with brine. The organiclayer was dried over Na₂SO₄, filtered, and concentrated to provide thetitle compound (43.0 mg, 78%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm8.46 (s, 1H), 8.32 (d, J=7.9 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.64 (d,J=7.9 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 5.71 (s,1H), 5.07 (d, J=12.4 Hz, 1H), 4.73 (d, J=12.3 Hz, 1H), 4.44 (d, J=11.4Hz, 1H), 4.28-4.10 (m, 3H), 4.00 (s, 3H), 3.73-3.57 (m, 2H), 2.48-2.47(m, 1H), 2.19 (dd, J=11.3, 3.5 Hz, 1H), 1.92-1.47 (m, 4H), 1.28 (t,J=7.1 Hz, 3H), 0.95 (s, 9H); MS (ESI+) m/z 657 & 659 (M+H)⁺.

Example 126E(2S,3R,4R,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 126D (40.0 mg, 0.061 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL), concentrated andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (29.6 mg, 55%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.69 (dq, J=8.4, 0.9 Hz, 1H),7.63 (dd, J=7.9, 1.5 Hz, 1H), 7.56 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.47(s, 1H), 7.39-7.31 (m, 2H), 6.49 (d, J=1.8 Hz, 1H), 5.76 (ddt, J=17.3,10.5, 5.3 Hz, 1H), 5.29 (d, J=6.5 Hz, 1H), 5.16-5.04 (m, 2H), 4.76 (p,J=6.5 Hz, 1H), 4.49-4.30 (m, 5H), 4.16-4.00 (m, 3H), 3.95 (s, 3H), 2.58(t, J=3.4 Hz, 1H), 1.35 (d, J=6.5 Hz, 3H), 1.28 (d, J=6.5 Hz, 3H), 1.13(t, J=7.1 Hz, 3H), 1.01 (s, 9H); MS (ESI+) m/z 629 & 631 (M+H)⁺.

Example 127(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedure described in Example144 substituting Core 19: for Core 10 and3-(bromomethyl)-5-trifluoromethyl-2-methoxypyridine for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.32 (d, J=2.3 Hz, 1H), 7.35 (s, 1H), 7.24 (s, 1H), 6.56(s, 1H), 5.65-5.47 (m, 1H), 4.70 (p, J=6.4 Hz, 1H), 4.62 (s, 1H),4.41-4.30 (m, 2H), 3.99 (d, J=13.8 Hz, 1H), 3.91 (s, 3H), 3.69 (dt,J=13.4, 6.9 Hz, 2H), 2.55 (s, 1H), 2.11-1.97 (m, 1H), 1.87-1.75 (m, 1H),1.76-1.64 (m, 2H), 1.38 (d, J=6.4 Hz, 3H), 1.29 (d, J=6.5 Hz, 3H), 1.26(s, OH), 1.01 (s, 9H), 0.91-0.78 (m, 1H); MS (APCI+) m/z 583 (M+H)⁺.

Example 128(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 128A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

Tetrahydropyran-2-carboxylic acid (53.7 mg, 0.413 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M in dichloromethane, 250 μL,0.50 mmol) was added followed by dimethylformamide (25 μL). The reactionwas stirred at room temperature for 3 hours, at which point it wasconcentrated, redissolved in dichloromethane (1 mL), and concentratedagain. The residue was taken up in dichloromethane (3×1 mL) and wasadded to a solution of Example 112E (90.4 mg, 0.174 mmol) andtriethylamine (100 μL, 0.717 mmol) in dichloromethane (3 mL). Thereaction was stirred at ambient temperature for 17 hours. After thistime, the mixture was diluted with dichloromethane (100 mL) and washedtwice with saturated aqueous NaHCO₃ and once with brine. The organiclayer was dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A). The title compound was the second eluting diastereomer andwas isolated as the TFA salt (43.7 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 8.27 (s, 1H), 7.96 (dd, J=7.6, 1.7 Hz, 1H), 7.16 (d,J=2.5 Hz, 1H), 7.06 (t, J=9.6 Hz, 2H), 6.95 (d, J=7.1 Hz, 1H), 5.90 (s,1H), 4.72 (s, 1H), 4.36 (d, J=5.6 Hz, 1H), 4.28 (d, J=13.9 Hz, 1H), 4.08(qd, J=7.1, 3.0 Hz, 2H), 3.89-3.80 (m, 5H), 3.75 (d, J=11.4 Hz, 1H),3.45 (s, 1H), 2.44 (d, J=1.8 Hz, 1H), 2.06-1.94 (m, 1H), 1.72-1.26 (m,6H), 1.13 (t, J=7.1 Hz, 3H), 1.04 (s, 9H), 0.99-0.84 (m, 2H), 0.80-0.67(m, 1H), 0.57-0.46 (m, 1H); MS (ESI+) m/z 633 (M+H)⁺.

Example 128B(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 128A (40.7 mg, 0.055 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction mixturewas quenched by the addition of 1M aqueous HCl (0.5 mL), concentratedand purified by reverse-phase preparative HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (27.3 mg, 70%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.27 (d, J=2.4 Hz, 1H), 8.02(dd, J=7.5, 1.8 Hz, 1H), 7.13 (s, 1H), 7.11-6.99 (m, 2H), 6.94 (dd,J=7.3, 1.7 Hz, 1H), 5.90 (s, 1H), 4.69 (s, 1H), 4.35 (d, J=5.8 Hz, 1H),4.31 (d, J=14.0 Hz, 1H), 3.95-3.84 (m, 5H), 3.76 (d, J=11.5 Hz, 1H),3.47 (s, 1H), 2.50 (d, J=1.8 Hz, 1H), 2.07-1.94 (m, 1H), 1.71-1.25 (m,6H), 1.04 (s, 9H), 0.98-0.84 (m, 2H), 0.78-0.65 (m, 1H), 0.49 (dtd,J=9.1, 5.3, 3.0 Hz, 1H); MS (ESI+) m/z 605 (M+H)⁺.

Example 129(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 129A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-nitro-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

To a mixture of Core 9 (946 mg, 2.83 mmol) in toluene (3 mL) andsaturated aqueous NaHCO₃ (3 mL) was added allyl carbonochloridate (360μL, 3.39 mmol) dropwise at room temperature. The mixture was stirred atroom temperature overnight. The reaction was poured into water (50 mL)and extracted with dichloromethane (50 mL). The organic layer was washedwith brine and concentrated in vacuo. Purification by silica gelchromatography, eluting with ethyl acetate in heptane, provided thetitle compound, 1.22 g (quantitative yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 7.79 (dd, J=7.8, 1.9 Hz, 1H), 7.24-7.04 (m, 3H), 5.69 (ddt, J=17.4,10.5, 5.1 Hz, 1H), 5.60 (d, J=8.9 Hz, 1H), 5.55 (dd, J=8.9, 3.1 Hz, 1H),5.07-4.96 (m, 2H), 4.56 (d, J=3.9 Hz, 1H), 4.42 (dtd, J=5.2, 1.7, 0.7Hz, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.08 (t, J=3.5 Hz, 1H), 2.36 (s, 3H),1.29 (td, J=7.1, 0.7 Hz, 3H), 1.03 (d, J=0.8 Hz, 9H); MS (ESI⁺) m/z419.0 (M+H)⁺.

Example 129B (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-oxo-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

Pyridinium dichromate (2.74 g, 7.29 mmol) was dissolved in 6N aqueousHCl (64.0 mL) and cooled in an ice bath. Zinc dust (5.24 g, 80 mmol) wasadded in portions, then the flask was removed from the ice bath, and thereaction mixture was stirred at room temperature for 75 minutes (untilzinc had dissolved and bubbling had stopped). The blue solution wastransferred via cannula over about 20 minutes to a refluxing solution ofExample 129A (1.22 g, 2.92 mmol) in ethanol (32 mL). The reactionmixture was refluxed overnight. The reaction mixture was cooled to roomtemperature, and extracted three times with dichloromethane. Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resulting material was taken up in 5.5 mL ofethanol and treated with a solution (prepared at 0° C.) of 1.85 mLacetyl chloride in 9 mL ethanol. The reaction mixture was refluxed for 1hour. After this time, the mixture was concentrated in vacuo, and theresidue was purified by silica gel chromatography, eluting with 0 to 40%ethyl acetate-heptanes to provide the title compound, 0.693 g, (61%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.68-7.61 (m, 1H), 7.21-7.06 (m,3H), 5.70 (m, 1H), 5.23 (s, 1H), 5.08-4.97 (m, 2H), 4.63 (d, J=5.1 Hz,1H), 4.46 (m, 2H), 4.28-4.18 (m, 2H), 2.64 (dd, J=5.3, 1.0 Hz, 1H), 2.38(s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.06 (s, 9H); MS (ESI⁺) m/z 388.0(M+H)⁺.

Example 129C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

A solution of Example 129B (0.693 g, 1.789 mmol) in ethanol (8.9 mL) wascooled to −10° and then treated with one portion of sodium borohydride(0.081 g, 2.146 mmol). The reaction stirred at −10° C. to −5° C. for 90minutes, and it was quenched carefully with 0.6 mL acetone. The mixturewas concentrated in vacuo, and the resulting material was taken up in 10mL ethyl acetate and stirred vigorously with 10 mL of saturated aqueousNaHCO₃ solution for 30 minutes. The mixture was transferred to aseparatory funnel, the phases were separated, and the aqueous layer wasextracted twice more with ethyl acetate (10 mL each). The combinedorganics were dried over Na₂SO₄, filtered, and concentrated in vacuo,and the crude product was purified by silica gel chromatography, elutingwith 5 to 40% ethyl acetate-heptanes to provide the title compound,0.280 g (40% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.85 (m, 1H),7.11-7.01 (m, 3H), 5.73-5.61 (m, 1H), 5.08 (d, J=6.6 Hz, 1H), 4.99 (m,2H), 4.45-4.33 (m, 3H), 4.30 (m, 1H), 4.22-4.12 (m, 2H), 3.82 (m, 1H),2.29 (s, 3H), 2.28 (m, 1H), 1.24 (t, J=7.1 Hz, 3H), 0.99 (s, 9H); MS(ESI+) m/z 390.1 (M+H)⁺.

Example 129D methyl 2-methoxy-5-(trifluoromethyl)nicotinate

To 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (50 g, 195 mmol) andPd-dppf (Heraeus) (1.32 g, 1.804 mmol) in a 300 mL stainless steelreactor was added methanol (250 mL) and triethylamine (54.4 mL, 391mmol). The reactor was degassed with nitrogen several times carbonmonoxide was added and the reaction was heated to 100±5° C., for about16.38 hours. The pressure was at 60 psi±4 psi for 2.7 hours and at 21±7psi for rest of the reaction time ˜14 hours. Additional Pd-dppf(Heraeus) (0.82 g, 1.121 mmol) catalyst was added. The reactor wasrepeatedly degassed with nitrogen several times, carbon monoxide wasadded and the reaction was heated to 100±5° C. for 10 hours. The crudeproduct was concentrated to remove methanol. Ethyl acetate (400 mL) wasadded, followed by the addition of 150 mL saturated aqueous NH₄Cl, andthe organic layer was isolated. The aqueous layer was extracted withethyl acetate (200 mL). The organic layers were combined, washed withbrine, dried over Na₂SO₄, filtered, and passed through a silica gel plugto remove dark Pt/C. The filtrate was concentrated to provide 40.62 g ofthe desired crude product, which was directly used in the next step. ¹HNMR (400 MHz, DMSO-d₆) δ ppm=3.84 (s, 3H) 3.96 (s, 3H) 8.40 (br s, 1H)8.81 (br s, 1H); MS (ESI⁺) m/z 236.1 (M+H)⁺.

Example 129E (2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol

Ethyl 2-methoxy-5-(trifluoromethyl)nicotinate (59.54 g, 253 mmol) wasdissolved in tetrahydrofuran (506 mL). After cooling to <5° C., asolution of lithium aluminum hydride (177 mL, 177 mmol) intetrahydrofuran was added over 40 minutes, maintaining an internaltemperature<10° C. After 1 hour, the reaction was quenched by theaddition of 50 mL of acetone then diluted with methyl tert-butyl ether(300 mL) and stirred with 300 mL of saturated aqueous Rochelle's salt(potassium sodium tartrate tetrahydrate) until two clear layers werepresent. The reaction mixture was extracted with ethyl acetate and thecombined extracts were washed with brine, dried over sodium sulfate,filtered, and concentrated. The crude material was purified by flashcolumn (0 to 30% ethyl acetate in heptane) to provide the title compound(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol (40.28 g, 194 mmol,77% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm=3.96 (s, 3H) 4.50 (d, J=5.73Hz, 2H) 5.45 (t, J=5.73 Hz, 1H) 7.89-8.01 (m, 1H) 8.47 (s, 1H); MS(ESI⁺) m/z 208.0 (M+H)⁺.

Example 129F 3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine

Example 129E (21.6 g, 104 mmol) and triphenylphosphine (54.7 g, 209mmol) were dissolved in dichloromethane (521 mL) and the reactionmixture was cooled to 0° C. N-bromosuccinimide (37.1 g, 209 mmol) wasadded in several portions and an exotherm/bubbling was noted(temperature did not exceed 25° C.). After stirring for 5 minutes in theice bath, the reaction was warmed to room temperature for 30 minutes.The reaction mixture was recooled in the ice bath before addition of 300mL of water, stirred for 5 minutes, and the organic layer was separated.The organic layer was washed with water (2×30 mL), concentrated toapproximately 50 mL and filtered through a fritted funnel layered with apad of silica (1.5 inch), eluting with heptanes. The filtrates wereconcentrated to provide a viscous mixture, diluted with 50:50 methyltert-butyl ether:heptanes and filtered. The filtrate was concentratedand purified with a 330 g silica gel cartridge using a gradient of 5%ethyl acetate in heptanes to provide desired product (22.12 g, 79%). ¹HNMR (400 MHz, CDCl₃) δ ppm=4.04-4.10 (m, 3H) 4.46-4.50 (m, 2H) 7.83 (d,J=2.43 Hz, 1H) 8.40 (d, J=1.10 Hz, 1H).

Example 129G (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate

Example 129C (0.280 g, 0.719 mmol), dried azeotropically with toluene,was dissolved in dimethylformamide (7.2 mL), and the solution was cooledto 0° C. Potassium 2-methylpropan-2-olate solution (1M intetrahydrofuran) (0.79 mL, 0.79 mmol) was added dropwise, followed bydropwise addition of Example 129F (0.233 g, 0.863 mmol). The reactionmixture stirred at 0° C. for 45 minutes, the mixture was poured into 30mL of saturated aqueous NH₄Cl solution and extracted three times withmethyl tert-butyl ether (3×30 mL). The combined organics were dried overNa₂SO₄, filtered and concentrated in vacuo, and the crude product waspurified by silica gel chromatography, eluting with 0 to 30% methyltert-butyl ether-heptanes to provide the title compound, 0.224 g (54%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.28 (m, 1H), 7.85 (tt, J=4.6,3.0 Hz, 0H), 7.18-7.13 (m, 1H), 7.04-6.96 (m, 3H), 5.69 (ddt, J=16.3,10.5, 5.1 Hz, 1H), 5.19 (d, J=5.8 Hz, 1H), 5.06-4.95 (m, 2H), 4.48 (d,J=2.3 Hz, 1H), 4.40 (dq, J=5.1, 1.5 Hz, 2H), 4.34-4.22 (m, 2H), 4.11 (q,J=7.0 Hz, 2H), 3.86 (s, 3H), 3.83 (dt, J=13.7, 1.1 Hz, 1H), 2.86-2.79(m, 1H), 2.51 (m, 1H), 2.31 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.03 (s,9H); MS (ESI⁺) m/z 578.9 (M+H)⁺.

Example 129H (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-2-carboxylate

Example 129G (0.224 g, 0.387 mmol) was dissolved in ethyl acetate (2 mL)and dichloromethane (2 mL), and the solution was treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.121 g, 0.774 mmol) andtetrakis(triphenylphosphine)palladium (4.5 mg, 3.87 μmol). The reactionstirred at room temperature overnight. After this time, the reactionmixture was diluted with methyl tert-butyl ether (20 mL) and stirredwith 20 mL of 10% aqueous Na₂CO₃ solution for 15 minutes. The phaseswere then separated, and the organic layer was washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. Silica gelchromatography, eluting with 0 to 30% methyl tert-butyl ether-heptanes,provided the title compound, 0.176 g (92% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.30 (s, 1H), 7.66-7.50 (m, 1H), 7.35 (d, J=2.4 Hz, 1H),7.05 (m, 3H), 4.34-4.10 (m, 5H), 4.10-3.99 (m, 1H), 3.86 (s, 3H), 3.79(d, J=13.9 Hz, 1H), 3.63 (s, 1H), 2.38 (dd, J=6.5, 1.7 Hz, 1H), 2.32 (s,3H), 1.21 (t, J=7.0 Hz, 3H), 0.99 (s, 9H); MS (APCI⁺) m/z 495.6 (M+H)⁺.

Example 129I (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example98A, substituting Example 129H for (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(Example 96E). The crude product was used in the next reaction withoutfurther purification. MS (APCI⁺) m/z 593.5 (M+H)⁺.

Example 129J(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure for Example98B, substituting Example 129F for Example 98A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.28 (s, 1H), 8.00 (d, J=5.5 Hz, 1H), 7.14 (s, 1H), 7.04(m, 3H), 5.53 (s, 1H), 4.66 (s, 1H), 4.34-4.25 (m, 2H), 4.05 (m, 1H),3.87 (d, J=14.0 Hz, 1H), 3.87 (s, 3H), 3.70-3.62 (m, 2H), 2.54 (m, 1H),2.33 (s, 3H), 1.97 (m, 1H), 1.79 (m, 1H), 1.64 (m, 2H), 1.03 (s, 9H); MS(ESI⁺) m/z 565.2 (M+H)⁺.

Example 130(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 130A methyl 5-cyclobutyl-2-methoxynicotinate

Methyl 5-bromo-2-methoxynicotinate (CombiBlocks, 2.516 g, 10.23 mmol)and PdCl₂(dppf) (0.383 g, 0.523 mmol) were suspended in tetrahydrofuran(100 mL), and the orange suspension was purged with N₂. A commercialsolution of cyclobutylzinc(II) bromide (Aldrich, 0.5 M tetrahydrofuran,24 mL, 12.00 mmol) was added dropwise, and the reaction was allowed tostir at room temperature for 16 hours. After this time, the reactionmixture was quenched by addition of 100 mL saturated aqueous ammoniumchloride, and the product was extracted into 300 mL of dichloromethane.The combined extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo. Silica gel chromatography, eluting with 5-100%ethyl acetate/heptanes, provided the title compound (1.110 g, 49%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.16 (d, J=2.6 Hz, 1H), 8.05 (d,J=2.6 Hz, 1H), 4.04 (s, 3H), 3.93 (s, 3H), 3.53 (p, J=8.6 Hz, 1H),2.43-2.33 (m, 2H), 2.21-2.01 (m, 3H), 1.96-1.88 (m, 1H); MS (ESI+) m/z222 (M+H)⁺.

Example 130B (5-cyclobutyl-2-methoxypyridin-3-yl)methanol

Example 130A (1.110 g, 5.02 mmol) was dissolved in tetrahydrofuran (24mL), and the solution was cooled in an ice bath. A solution of lithiumaluminum hydride (2M in tetrahydrofuran, 2.51 mL, 5.02 mmol) was addeddropwise over 3 minutes via syringe. The reaction mixture was dilutedwith 200 mL of methyl tert-butyl ether and quenched with 10 mL ofsaturated aqueous Rochelle's salt (potassium sodium tartratetetrahydrate). The mixture was stirred for another 30 minutes at roomtemperature before separating the layers. The organic layer was driedover sodium sulfate and filtered. The solvent was removed to provide thetitle compound, 0.943 g (97% yield). The compound was driedazeotropically with toluene and used directly in the next reaction. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.94 (d, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz,1H), 4.67 (d, J=6.3 Hz, 2H), 4.00 (d, J=0.8 Hz, 3H), 3.51 (p, J=8.5 Hz,1H), 2.36 (dtd, J=10.3, 8.0, 2.7 Hz, 2H), 2.29 (t, J=6.5 Hz, 1H),2.22-2.00 (m, 3H), 1.97-1.84 (m, 1H); MS (ESI+) m/z 194 (M+H)⁺.

Example 130C 3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine

Example 130B (0.943 g, 4.88 mmol) and triphenylphosphine (2.56 g, 9.76mmol) were dissolved in dichloromethane (24.4 mL) and cooled in an icebath. N-bromosuccinimide (1.737 g, 9.76 mmol) was added gradually usinga solid addition funnel, keeping the internal temperature below 10° C.After completion of the addition, the ice bath was removed, and thereaction was stirred at room temperature for 15 minutes. Water was added(10 mL), and the mixture was stirred for 5 minutes before the layerswere separated. The organic layer was washed twice with water and thenfiltered through a fritted cartridge layered with a pad of silica (1cm), eluting with heptanes. The filtrates were reduced in volume. Thematerial was collected by filtration and washed with 3×30 mL of 50:50methyl tert-butyl ether:heptanes. The filtrate was concentrated, and theresidue was purified by silica gel chromatography, eluting with 5-50%ethyl acetate/heptanes, to provide the title compound (1.07 g, 86%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (d, J=2.4 Hz, 1H), 7.52 (d,J=2.4 Hz, 1H), 4.52 (s, 2H), 4.02 (s, 3H), 3.59-3.38 (m, 1H), 2.44-2.31(m, 2H), 2.21-2.00 (m, 3H), 1.95-1.85 (m, 1H); MS (ESI+) m/z 256 (M+H)⁺.

Example 130D (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

Core 13 (18.1 g, 49.9 mmol) was dissolved in toluene (125 mL), andsaturated aqueous sodium bicarbonate (125 mL) was added. After coolingto approximately 10° C., the mixture was treated with allylchloroformate (5.59 mL, 52.4 mmol), and the flask was removed from thebath. The reaction mixture was stirred overnight at room temperature.The phases were separated, and the aqueous layer was extracted withadditional methyl tert-butyl ether. The combined organics were washedtwice with water, dried over Na₂SO₄, filtered and concentrated in vacuo.The title compound thus obtained (22 g, 99% yield) was used directly inthe next reaction without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.86 (dd, J=7.9, 1.2 Hz, 1H), 7.24-7.15 (m, 2H), 7.05(ddd, J=8.3, 6.5, 2.1 Hz, 1H), 5.76-5.60 (m, 2H), 5.53 (dd, J=8.9, 3.6Hz, 1H), 5.06-4.93 (m, 2H), 4.55 (d, J=4.3 Hz, 1H), 4.41 (dt, J=5.2, 1.6Hz, 2H), 4.32-4.22 (m, 2H), 3.24 (hept, J=6.7 Hz, 1H), 3.13-3.06 (m,1H), 1.36-1.22 (m, 6H), 1.19 (dd, J=6.6, 0.8 Hz, 3H), 1.03 (s, 9H); MS(ESI⁺) m/z 447.0 (M+H)⁺.

Example 130E (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

The title compound was prepared according to the procedure of Example17B, substituting Example 130D for Example 17A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.70 (m, 1H), 7.31 (m, 1H), 7.19 (m, 1H), 7.09 (m, 1H),5.75-5.60 (m, 1H), 5.35 (s, 1H), 5.09-4.92 (m, 2H), 4.63 (d, J=5.5 Hz,1H), 4.45 (m, 2H), 4.23 (m, 2H), 3.32 (m, 1H), 2.65 (m, 1H), 1.33-1.14(m, 9H), 1.10-0.97 (m, 9H); MS (ESI⁺) m/z 415.8 (M+H)⁺.

Example 130F (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropylphenyl)pyrrolidine-1,2-dicarboxylate

The title compound was prepared according to the procedure of Example129C, substituting Example 130E for Example 129B. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.90 (dd, J=7.8, 1.5 Hz, 1H), 7.24-7.00 (m, 3H),5.72-5.52 (m, 1H), 5.22 (d, J=6.6 Hz, 1H), 5.03-4.91 (m, 2H), 4.44-4.27(m, 4H), 4.18 (m, 2H), 3.72 (m, 1H), 3.20 (m, 1H), 2.29 (t, J=4.2 Hz,1H), 1.29-1.16 (m, 9H), 1.04 (s, 1H), 1.00 (s, 9H); MS (APCI⁺) m/z 418.3(M+H)⁺.

Example 130G (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropylphenyl)pyrrolidine-1,2-dicarboxylate

The title compound was prepared according to the procedure of Example100E, substituting Example 130C for Example 100D and substitutingExample 130F for Example 100C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.94 (d,J=7.9 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.25-7.08 (m, 2H), 7.03 (t, J=7.6Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 5.65 (m, 1H), 5.30 (d, J=5.7 Hz, 1H),5.05-4.88 (m, 2H), 4.47 (d, J=2.2 Hz, 1H), 4.38 (m, 2H), 4.24-4.02 (m,4H), 3.77 (m, 1H), 3.73 (s, 3H), 3.42-3.13 (m, 2H), 2.50 (m, 1H),2.35-2.14 (m, 2H), 2.05-1.78 (m, 4H), 1.22 (d, J=6.8 Hz, 3H), 1.18 (d,J=6.8 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.02 (s, 9H); MS (ESI⁺) m/z 593.3(M+H)⁺.

Example 130H (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropylphenyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure for Example129H, substituting Example 130G for Example 129G. The crude product wastaken directly into the next reaction without further purification. MS(ESI⁺) m/z 509.4 (M+H)⁺.

Example 130I (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropylphenyl)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example98A, substituting Example 13 OH for (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(Example 96E). The crude product was taken directly into the nextreaction without further purification. MS (APCI⁺) m/z 607.7 (M+H)⁺.

Example 130J(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure of Example98B, substituting Example 1301 for Example 98A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.04 (d, J=7.8 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.21 (dd,J=18.1, 7.4 Hz, 2H), 7.06 (t, J=7.5 Hz, 1H), 6.83 (s, 1H), 5.64 (m, 1H),4.68 (m, 1H), 4.26-4.16 (m, 2H), 4.06 (m, 1H), 3.83-3.64 (m, 5H), 3.59(m, 1H), 3.35-3.18 (m, 2H), 2.52 (m, 1H), 2.23 (m, 2H), 2.02-1.74 (m,6H), 1.62 (m, 2H), 1.25 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H), 1.02(s, 9H); MS (ESI⁺) m/z 579.2 (M+H)⁺.

Example 131(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 131A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)-1-((R)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

Tetrahydropyran-2-carboxylic acid (57.8 mg, 0.444 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M in dichloromethane, 300 μL,0.60 mmol) was added followed by dimethylformamide (25 μL). The reactionwas stirred at room temperature for 3 hours, at which point it wasconcentrated, redissolved in dichloromethane (1 mL), and concentratedagain. The residue was taken up in dichloromethane (3×1 mL) and added toa solution of Example 116B (107.9 mg, 0.214 mmol) and triethylamine (100μL, 0.717 mmol) in dichloromethane (3 mL). The reaction mixture wasstirred at ambient temperature for 17 hours. After this time, themixture was diluted with dichloromethane (100 mL) and washed twice withsaturated aqueous NaHCO₃ and once with brine. The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby reverse-phase preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 ÅPrep-Pak® cartridge column (40 mm×100 mm) and eluting with a gradient of10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12minutes, at a flow rate of 70 mL/minute. The title compound was thefirst eluting diastereomer (58.8 mg, 45%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 7.86 (s, 1H), 7.66 (dq, J=8.4, 0.9 Hz, 1H), 7.53 (ddd,J=8.4, 6.9, 1.5 Hz, 1H), 7.48 (dd, J=8.0, 1.5 Hz, 1H), 7.33 (ddd, J=8.1,6.9, 1.3 Hz, 1H), 7.21 (d, J=7.6 Hz, 2H), 7.09 (d, J=16.6 Hz, 2H), 5.41(d, J=5.6 Hz, 1H), 4.97 (s, 1H), 4.35 (dd, J=14.0, 1.3 Hz, 1H), 4.23 (d,J=5.6 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.98-3.87 (m, 4H), 3.82 (s, 1H),3.24 (h, J=6.8 Hz, 1H), 2.69-2.58 (m, 1H), 2.50 (s, 1H), 1.80 (s, 1H),1.66-1.33 (m, 5H), 1.26 (d, J=6.7 Hz, 3H), 1.18-1.09 (m, 6H), 1.05 (s,9H); MS (ESI+) m/z 617 (M+H)⁺.

Example 131B(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 131A (55.8 mg, 0.090 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL), concentrated andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (21.1 mg, 33%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.91 (s, 1H), 7.65 (d, J=8.3Hz, 1H), 7.57-7.48 (m, 2H), 7.33 (ddd, J=7.9, 6.8, 1.2 Hz, 1H), 7.20 (q,J=8.0 Hz, 2H), 7.14 (s, 1H), 7.04 (t, J=7.4 Hz, 1H), 5.41 (d, J=5.7 Hz,1H), 4.94 (s, 1H), 4.37 (dd, J=14.2, 1.3 Hz, 1H), 4.22 (d, J=5.7 Hz,1H), 3.98-3.89 (m, 6H), 3.84 (s, 1H), 3.24 (hept, J=6.7 Hz, 1H), 2.69(s, 1H), 1.80 (s, 1H), 1.68-1.33 (m, 5H), 1.27 (d, J=6.7 Hz, 3H), 1.13(d, J=6.8 Hz, 3H), 1.05 (s, 9H); MS (ESI+) m/z 589 (M+H)⁺.

Example 132(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 132A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

Tetrahydropyran-2-carboxylic acid (57.8 mg, 0.444 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M in dichloromethane, 300 μL,0.60 mmol) was added followed by dimethylformamide (25 μL). The reactionwas stirred at room temperature for 3 hours, at which point it wasconcentrated, redissolved in dichloromethane (1 mL), and concentratedagain. The residue was taken up in dichloromethane (3×1 mL) and added toa solution of Example 116B (107.9 mg, 0.214 mmol) and triethylamine (100μL, 0.717 mmol) in dichloromethane (3 mL). The reaction was stirred atambient temperature for 17 hours. After this time, the mixture wasdiluted with dichloromethane (100 mL) and washed twice with saturatedaqueous NaHCO₃ and once with brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified byreverse-phase preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 ÅPrep-Pak® cartridge column (40 mm×100 mm), eluting with a gradient of10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12minutes, at a flow rate of 70 mL/minute. The title compound was thesecond eluting diastereomer (58.2 mg, 44%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 8.06 (d, J=7.9 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.58-7.45(m, 2H), 7.37-7.21 (m, 3H), 7.13 (s, 2H), 5.64 (s, 1H), 4.75 (d, J=1.8Hz, 1H), 4.36 (d, J=13.9 Hz, 1H), 4.26 (d, J=5.7 Hz, 1H), 4.09 (q, J=7.1Hz, 2H), 3.97-3.88 (m, 4H), 3.78-3.71 (m, 1H), 3.25 (hept, J=6.9 Hz,1H), 3.18-2.98 (m, 2H), 2.50 (d, J=1.9 Hz, 1H), 1.73-1.49 (m, 2H),1.48-1.23 (m, 7H), 1.17-1.08 (m, 6H), 1.05 (s, 9H); MS (ESI+) m/z 617(M+H)⁺.

Example 132B(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 132A (55.2 mg, 0.089 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL), concentrated, andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (33.1 mg, 53%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.11 (d, J=7.9 Hz, 1H), 7.66(d, J=8.3 Hz, 1H), 7.57-7.47 (m, 2H), 7.33 (ddd, J=8.0, 7.0, 1.3 Hz,1H), 7.26 (d, J=8.1 Hz, 2H), 7.14 (d, J=15.2 Hz, 2H), 5.65 (s, 1H), 4.73(d, J=1.7 Hz, 1H), 4.39 (d, J=14.1 Hz, 1H), 4.26 (d, J=5.8 Hz, 1H), 3.94(dd, J=14.1, 1.4 Hz, 1H), 3.91 (s, 3H), 3.76 (d, J=11.3 Hz, 1H), 3.64(s, 1H), 3.24 (h, J=6.9 Hz, 1H), 3.10 (s, 1H), 2.57 (d, J=1.6 Hz, 1H),1.74-1.52 (m, 2H), 1.37 (d, J=10.2 Hz, 4H), 1.30 (d, J=6.7 Hz, 3H), 1.10(d, J=6.8 Hz, 3H), 1.05 (s, 9H); MS (ESI+) m/z 589 (M+H)⁺.

Example 133(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 133A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-methoxypyridin-3-yl)-4-nitropyrrolidine-1,2-dicarboxylate

To a mixture of Core 12 (5.0 g, 14.23 mmol) in toluene (30 mL) andsaturated aqueous NaHCO₃ (30 mL) was added allyl carbonochloridate (3.78mL, 35.6 mmol) dropwise at ambient temperature and the mixture wasstirred for 1 hour. Ethyl acetate (30 mL) was added. The organic layerwas washed with brine, dried over MgSO₄, filtered, and concentrated.Purification of the residue via chromatography on a 80 g silica gelcartridge, eluting with ethyl acetate in heptanes at 0-40% gradientprovided the title compound (5.4 g, 87% yield). LC/MS (APCI+) m/z 436.41(M+H)⁺.

Example 133B (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-hydroxypyridin-3-yl)-4-oxopyrrolidine-1,2-dicarboxylate

A solution of CrCl₂ was prepared by dissolving pyridinium dichromate(10.80 g, 28.7 mmol) in aqueous hydrochloric acid, (6 M, 207 mL) andadding Zn (20.27 g, 310 mmol) in portions over 20 minutes while coolingin an ice bath, maintaining the internal temperature below 35° C. Theresulting suspension was stirred at room temperature for 30 minutesafter removing from the ice bath, leaving a brilliant blue solution. Ina separate flask, Example 133A (5 g, 11.48 mmol) was dissolved inethanol (103 mL) and the resulting solution was heated to 75° C. TheCrCl₂ solution was added via addition funnel over 20 minutes to thesolution of the starting material, and the temperature was increased to85° C. after the addition was complete. Heating was continued for 16hours at the same temperature, at which point the intermediate oxime hadbeen fully consumed. A mixture of the title compound and(2S,3R,5S)-1-((allyloxy)carbonyl)-3-(tert-butyl)-5-(2-hydroxypyridin-3-yl)-4-oxopyrrolidine-2-carboxylicacid was produced at this point. The reaction mixture was cooled toambient temperature and poured into a separatory funnel. The productmixture was extracted into 3×100 mL of dichloromethane and the combinedextracts were dried over sodium sulfate, filtered and concentrated toprovide a crude material (4.5 g), which was re-esterified according tothe following procedure: The crude material (4.5 g) was dissolved in asolution of HCl-ethanol prepared by addition of acetyl chloride (4.08mL, 57.4 mmol) to ethanol (45.9 mL) while cooling in an ice-water bath.The resulting yellow solution was heated to 45° C. for 3 hours, at whichpoint complete re-esterification had occurred. The flask was cooled toambient temperature, concentrated in vacuo and partitioned betweensaturated aqueous sodium bicarbonate and ethyl acetate. The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered, and concentrated to provide the title compound (3.5 g), whichwas used without additional purification. ¹H NMR (400 MHz, DMSO-d₆) δppm 11.23 (br s, 1H), 7.52 (dd, J=6.7, 2.1 Hz, 1H), 7.30-7.08 (m, 2H),6.14 (t, J=6.6 Hz, 1H), 5.86 (ddt, J=17.3, 10.5, 5.3 Hz, 1H), 5.26-5.09(m, 2H), 4.77-4.51 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 1.13 (t, J=7.1 Hz,3H), 1.02 (s, 9H); MS (ESI+) m/z 391.2 (M+H)⁺.

Example 133C (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-oxopyrrolidine-1,2-dicarboxylate

Example 133B (3.4 g, 8.71 mmol) was dissolved in 35 mL of chloroform.Silver carbonate (4.80 g, 17.42 mmol) was added, followed by2-iodopropane (2.61 mL, 26.1 mmol) and the reaction mixture was heatedto 60° C. for 3.5 hours. The reaction mixture was cooled to ambienttemperature, diluted with methyl tert-butyl ether (50 mL), filteredthrough diatomaceous earth, and concentrated to provide 3.8 g of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.04 (dd, J=4.9, 1.9 Hz,1H), 7.86 (dd, J=7.4, 1.9 Hz, 1H), 6.88 (dd, J=7.4, 4.9 Hz, 1H),5.84-5.69 (m, 1H), 5.28-5.19 (m, 1H), 5.17-5.06 (m, 3H), 4.64 (d, J=4.2Hz, 1H), 4.49 (dt, J=5.2, 1.6 Hz, 2H), 4.18 (qd, J=7.1, 3.0 Hz, 2H),2.67 (dd, J=4.3, 0.9 Hz, 1H), 1.29 (d, J=6.1 Hz, 3H), 1.22 (d, J=6.1 Hz,3H), 1.20 (t, J=6.7 Hz, 3H), 1.06 (s, 9H); MS (ESI+) m/z 433.3 (M+H)⁺.

Example 133D (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylateand Example 133E (2S,3R,4R,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

Example 133C (3.77 g, 8.72 mmol) was dissolved in ethanol (43.6 mL) andthe solution was cooled to ˜−10° C. before addition of sodiumborohydride (0.429 g, 11.33 mmol) in small portions over 2 minutes.After stirring for 45 minutes at the same temperature, TLC indicatedcomplete conversion to the desired mixture of alcohols. Acetone (5 mL)was added slowly due to delayed exotherms to quench the excess reducingagent, and the reaction was warmed to ambient temperature. The mixturewas concentrated in vacuo and diluted with a mixture of methyltert-butyl ether and saturated sodium bicarbonate (50 mL each). Themixture was stirred for 30 minutes at ambient temperature and the layerswere separated. The product was extracted into methyl tert-butyl ether(2×25 mL) and the combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated to provide thecrude material. The crude material was purified via flashchromatography, eluting on an 80 g silica gel column with 0:100 to 10:90ethyl acetate:heptanes over 5 minutes, isocratic 10:90 ethylacetate:heptanes until complete elution of the first diastereomer((2S,3R,4R,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate,Example 133E) which was isolated as a mixture of compounds, and thegradient was increased to 20:80 ethyl acetate:heptanes over 10 minutesand maintained at 20:80 ethyl acetate:heptanes until complete elution ofthe second diastereomer (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate(1.79 g, Example 133D). For Example 133D (second eluent) ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.06-7.82 (m, 2H), 6.83 (dd, J=7.4, 4.9 Hz, 1H),5.71 (ddt, J=18.8, 10.2, 5.1 Hz, 1H), 5.27 (p, J=6.1 Hz, 1H), 5.13-4.89(m, 2H), 4.46-4.27 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 4.00 (d, J=6.6 Hz,1H), 2.26 (t, J=2.7 Hz, 1H), 1.32 (d, J=6.1 Hz, 3H), 1.29 (d, J=6.2 Hz,3H), 1.23 (t, J=7.1 Hz, 3H), 1.11 (s, 3H), 0.99 (s, 9H); MS (ESI+) m/z435.3 (M+H). For Example 133E (first eluting,) MS (ESI+) m/z 435.3(M+H)⁺.

Example 133F (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

Example 133D (1.79 g, 4.12 mmol) was dissolved in 20 mL of drydimethylformamide and the solution was cooled to <5° C. before dropwiseaddition of potassium tert-butoxide (1 M in tetrahydrofuran, 4.53 mL,4.53 mmol). After the addition was completed,3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (1.266 g, 4.94 mmol) wasadded dropwise as a solution in 1 mL tetrahydrofuran and the reactionwas stirred at the same temperature for 5 minutes. The reaction wasquenched with saturated aqueous ammonium chloride (10 mL) and extractedwith methyl tert-butyl ether (3×10 mL). The combined organic extractswere washed with water (20 mL) and brine (20 mL). The organics wereconcentrated in vacuo and purified via flash chromatography, elutingwith 0:100 to 30:70 ethyl acetate:heptanes to provide 1.79 g of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03 (ddd, J=7.4, 1.9,0.8 Hz, 1H), 7.95 (dd, J=5.0, 2.0 Hz, 1H), 7.77 (dd, J=2.4, 0.8 Hz, 1H),6.87-6.79 (m, 2H), 5.82-5.66 (m, 1H), 5.30-5.18 (m, 2H), 5.13-5.00 (m,2H), 4.49 (d, J=2.4 Hz, 1H), 4.32-4.26 (m, 2H), 4.11-4.00 (m, 2H),3.99-3.92 (m, 1H), 3.76 (s, 3H), 3.36-3.30 (m, 1H), 2.47-1.77 (m, 6H),1.30 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.1 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H),1.12 (t, J=7.1 Hz, 3H), 1.02 (s, 9H); MS (ESI⁺) m/z 610.5 (M+H)⁺.

Example 133G (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate

Example 133F (1.78 g, 2.92 mmol) was dissolved in a mixture ofdichloromethane (14.60 mL) and ethyl acetate (14.60 mL).1,3-Dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.912 g, 5.84 mmol) wasadded, followed by tetrakis(triphenylphosphine)palladium (0.034 g, 0.029mmol) and the reaction mixture was stirred at ambient temperature for 10minutes, at which point complete conversion was achieved. The mixturewas diluted with methyl tert-butyl ether (50 mL), 10% sodium carbonate(50 mL) was added, and the mixture was stirred for 10 minutes. Thelayers were separated, the aqueous layer was extracted with methyltert-butyl ether (3×25 mL), and the combined organic extracts werewashed with brine (50 mL). The organics were dried over sodium sulfate,filtered, and concentrated to provide the title compound, which was usedwithout additional purification. MS (ESI+) m/z 526.5 (M+H)⁺.

Example 133H(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 121G, substituting (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate(Example 133G) for Example 121F. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.42(s, 1H), 7.95 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 6.79 (d, J=14.1 Hz, 2H),4.45 (s, 1H), 4.32 (d, J=13.2 Hz, 1H), 4.22 (s, 1H), 4.00 (d, J=13.5 Hz,1H), 3.78 (s, 1H), 3.77 (d, J=1.0 Hz, 3H), 3.66 (s, 1H), 3.32 (q, J=8.5Hz, 1H), 2.63 (s, 2H), 2.27-2.17 (m, 2H), 2.00-1.79 (m, 6H), 1.28 (d,J=6.0 Hz, 3H), 1.18 (d, J=6.1 Hz, 3H), 1.05-0.93 (m, 9H); MS (ESI+) m/z596 (M+1)⁺.

Example 134(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(oxane-4-carbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 121G, substituting Example 133G for Example 121F, andtetrahydro-2H-pyran-4-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.19 (s, 1H), 7.97 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 6.82 (s, 2H), 5.36(s, 1H), 5.26 (p, J=6.1 Hz, 1H), 4.53 (d, J=2.8 Hz, 1H), 4.30 (d, J=13.1Hz, 1H), 4.25 (dd, J=6.3, 2.1 Hz, 1H), 3.98 (d, J=13.2 Hz, 1H), 3.82(dt, J=11.2, 3.5 Hz, 1H), 3.76 (s, 3H), 3.32 (p, J=8.4 Hz, 2H), 2.56 (s,1H), 2.35-2.17 (m, 3H), 2.11-1.79 (m, 6H), 1.57 (s, 4H), 1.32 (d, J=6.1Hz, 3H), 1.22 (d, J=6.1 Hz, 3H), 0.99 (s, 9H); MS (ESI+) m/z 610.2(M+H)⁺.

Example 135(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 135A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)-1-((R)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylateand Example 135B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To tetrahydro-2H-pyran-2-carboxylic acid (CAS#51673-83-7) (89 mg, 0.685mmol) and a drop of dimethylformamide in dichloromethane (6 mL) wasadded oxalyl dichloride (130 mg, 1.027 mmol, 0.5 mL, 2M indichloromethane). The mixture was stirred for 30 minutes. The solventwas removed under pressure and fresh dichloromethane was added andremoved again. The residue was dissolved in dichloromethane (1 mL) andadded dropwise to the solution of Example 133G (180 mg, 0.342 mmol) andtriethylamine (0.191 mL, 1.370 mmol) in dichloromethane (6 mL) in anice-bath. The mixture was stirred at 0° C. for 30 minutes, and allowedto warm to ambient temperature. Dichloromethane and saturated aqueousNH₄Cl were added and the organic layer was washed with brine, dried overMgSO₄, filtered, and concentrated. Purification of the residue bychromatography, eluting with ethyl acetate in heptanes at 0-40% gradientprovided (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)-1-((R)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(Example 135A, 65 mg, 29.8% yield) as the first eluent. LC/MS (APCI+)m/z 638.8 (M+H)⁺. (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(Example 135B, 50 mg, 22.89% yield) was obtained as the second eluent.LC/MS (APCI+) m/z 638.8 (M+H)⁺.

Example 135C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The mixture of Example 135A (60 mg, 0.094 mmol) in methanol (1.5 mL) and6M aqueous LiOH (0.5 mL) was stirred at 45° C. for overnight. LC/MSindicated conversion was finished. The mixture was adjusted to pH to 1˜2using 2N aqueous HCl and was purified by chromatography on a 12 g silicagel cartridge eluting with methanol in dichloromethane at 0-20% gradientto provide the title compound 41 mg (71.5% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.93 (d, J=4.6 Hz, 2H), 7.76 (d, J=2.4 Hz, 1H), 6.79 (s,2H), 5.24 (dd, J=12.9, 6.8 Hz, 2H), 4.94 (s, 1H), 4.30 (d, J=13.2 Hz,1H), 4.24 (dd, J=6.0, 1.2 Hz, 1H), 3.94 (d, J=13.3 Hz, 3H), 3.76 (s,3H), 3.31 (p, J=8.3 Hz, 1H), 2.86-2.81 (m, 1H), 2.58 (s, 1H), 2.22 (ddt,J=6.3, 4.9, 3.3 Hz, 2H), 2.04-1.85 (m, 4H), 1.86-1.74 (m, 2H), 1.49 (d,J=43.0 Hz, 4H), 1.31 (d, J=6.1 Hz, 3H), 1.20 (d, J=6.1 Hz, 3H), 1.00 (s,9H); MS (ESI+) m/z 610.2 (M+H)⁺.

Example 136(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

(2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(Example 135B, 45 mg, 0.071 mmol) dissolved in methanol (1.5 mL) and 6Naqueous NaOH (0.5 mL) was stirred at 45° C. for overnight. The mixtureadjusted pH to 1˜2 by 2N aqueous HCl and the mixture was purified bychromatography, eluting with methanol in CH₂Cl₂ at 0-20% gradient toyield title compound (33 mg, 0.054 mmol, 77% yield)¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.35 (s, 1H), 7.96 (s, 1H), 7.76 (d, J=2.5 Hz, 1H), 6.82(d, J=2.6 Hz, 2H), 5.65 (s, 1H), 5.24 (dq, J=11.6, 5.9 Hz, 1H), 4.56 (s,1H), 4.30 (d, J=13.2 Hz, 1H), 4.21 (dd, J=6.5, 2.2 Hz, 1H), 3.98 (d,J=13.2 Hz, 1H), 3.85 (s, 1H), 3.80 (d, J=10.8 Hz, 1H), 3.76 (s, 3H),3.33 (q, J=8.1 Hz, 2H), 2.52 (s, 1H), 2.25-2.21 (m, 1H), 1.96-1.79 (m,5H), 1.74-1.34 (d, J=62.2 Hz, 6H), 1.32 (d, J=6.2 Hz, 3H), 1.19 (d,J=6.1 Hz, 3H), 0.98 (s, 9H); MS (ESI+) m/z 610.2 (M+1)⁺.

Example 137(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 137A 2-ethyl 1-isopropyl(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxyquinolin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 86C (72.2 mg, 0.158 mmol) and Example 106B (60.0 mg, 0.238 mmol)were dissolved in dimethylformamide (1.5 mL). The reaction was cooled to0° C., then potassium tert-butoxide (1M in tetrahydrofuran, 0.20 mL,0.20 mmol) was added dropwise and the reaction was stirred at ambienttemperature for 1 hour. The reaction was quenched by the addition of 1Maqueous HCl (0.1 mL) and purified by silica gel chromatography (0% to 5%ethyl acetate in dichloromethane) to provide the title compound (43.6mg, 37%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.03 (dd, J=7.8, 1.7Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.55 (td, J=8.4, 1.7 Hz, 2H), 7.47 (dd,J=8.1, 1.2 Hz, 1H), 7.39-7.23 (m, 3H), 7.14 (td, J=7.6, 1.8 Hz, 1H),5.31 (d, J=5.7 Hz, 1H), 4.67 (hept, J=6.2 Hz, 1H), 4.48 (d, J=2.1 Hz,1H), 4.43-4.34 (m, 2H), 4.13 (qd, J=7.1, 0.8 Hz, 2H), 4.06 (d, J=13.4Hz, 1H), 3.92 (d, J=0.8 Hz, 3H), 2.56-2.49 (m, 1H), 1.16 (td, J=7.1, 0.8Hz, 3H), 1.07 (d, J=6.2 Hz, 3H), 1.03 (d, J=0.8 Hz, 9H), 0.90 (d, J=6.2Hz, 3H); MS (ESI+) m/z 627 & 629 (M+H)⁺.

Example 137B(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 137A (40.6 mg, 0.055 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL) and purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound (22.2 mg, 57%) as the TFA salt. ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.10 (dd, J=7.9, 1.7 Hz, 1H), 7.67 (d,J=8.1 Hz, 1H), 7.55 (t, J=7.5 Hz, 2H), 7.47 (d, J=7.9 Hz, 1H), 7.35 (t,J=7.5 Hz, 1H), 7.31-7.25 (m, 2H), 7.16-7.09 (m, 1H), 5.31 (d, J=5.8 Hz,1H), 4.66 (hept, J=6.3 Hz, 1H), 4.44 (d, J=2.0 Hz, 1H), 4.42-4.35 (m,2H), 4.06 (dd, J=13.8, 1.2 Hz, 1H), 3.92 (s, 3H), 2.57 (t, J=1.4 Hz,1H), 1.07 (d, J=6.2 Hz, 3H), 1.03 (s, 9H), 0.90 (d, J=6.2 Hz, 3H); MS(ESI+) m/z 599 & 601 (M+H)⁺.

Example 138(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 138A 2-ethyl 1-isopropyl(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 86C (81.3 mg, 0.178 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (70.6 mg, 0.276 mmol)were dissolved in dimethylformamide (1.5 mL). The reaction was cooled to0° C., potassium tert-butoxide (1M in tetrahydrofuran, 0.20 mL, 0.20mmol) was added dropwise, and the reaction mixture was stirred atambient temperature for 1 hour. The reaction was quenched by theaddition of 1M aqueous HCl (0.1 mL) and purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound (44.5 mg, 34%) as the TFA salt. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 7.99 (dd, J=7.9, 1.8 Hz, 1H), 7.77 (d, J=2.4 Hz,1H), 7.47 (dd, J=8.0, 1.3 Hz, 1H), 7.25 (td, J=7.6, 1.3 Hz, 1H), 7.11(td, J=7.6, 1.8 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 5.27 (d, J=5.7 Hz, 1H),4.65 (hept, J=6.2 Hz, 1H), 4.45 (d, J=2.1 Hz, 1H), 4.33 (dd, J=5.7, 1.3Hz, 1H), 4.22 (d, J=13.0 Hz, 1H), 4.11 (qd, J=7.0, 1.0 Hz, 2H), 3.91(dt, J=13.0, 0.8 Hz, 1H), 3.75 (s, 3H), 3.38-3.28 (m, 1H), 2.48 (s, 1H),2.25 (dddd, J=12.1, 8.6, 4.9, 2.5 Hz, 2H), 2.05-1.79 (m, 4H), 1.15 (t,J=7.0 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.01 (s, 9H), 0.89 (d, J=6.2 Hz,3H); MS (ESI+) m/z 631 & 633 (M+H)⁺.

Example 138B(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 138A (41.5 mg, 0.056 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction mixturewas quenched by the addition of 1M aqueous HCl (0.5 mL) and purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound (28.0 mg, 70%) as the TFA salt. ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.05 (dd, J=7.9, 1.7 Hz, 1H), 7.77 (d,J=2.4 Hz, 1H), 7.46 (dd, J=8.0, 1.2 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H),7.10 (td, J=7.6, 1.7 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 5.27 (d, J=5.8 Hz,1H), 4.64 (hept, J=6.3 Hz, 1H), 4.40 (d, J=2.1 Hz, 1H), 4.31 (dd, J=5.8,1.1 Hz, 1H), 4.24 (d, J=13.1 Hz, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.76 (s,3H), 3.33 (p, J=8.5 Hz, 1H), 2.50 (t, J=1.5 Hz, 1H), 2.33-2.19 (m, 2H),1.99-1.77 (m, 4H), 1.06 (d, J=6.2 Hz, 3H), 1.01 (s, 9H), 0.88 (d, J=6.2Hz, 3H); MS (ESI+) m/z 603 & 605 (M+H)⁺.

Example 139(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 139A 1-allyl 2-ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 112C (324 mg, 0.780 mmol) and Example 106B (205.6 mg, 1.046mmol) were dissolved in dimethylformamide (2.5 mL). The reaction wascooled to 0° C., then potassium tert-butoxide (1M in tetrahydrofuran,1.00 mL, 1.00 mmol) was added dropwise and the reaction was stirred atambient temperature for 1 hour. The reaction mixture was poured intosaturated aqueous NH₄Cl (35 mL) and extracted with methyl tert-butylether (3×35 mL). The organic layer was concentrated and the crudematerial was purified by silica gel chromatography (0% to 5% ethylacetate in dichloromethane) to provide the title compound (378.4 mg,83%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.99-7.91 (m, 1H), 7.66(d, J=8.3 Hz, 1H), 7.57-7.48 (m, 2H), 7.34 (ddd, J=8.0, 6.8, 1.2 Hz,1H), 7.19-7.10 (m, 3H), 7.01-6.94 (m, 1H), 5.75-5.61 (m, 2H), 5.07-4.92(m, 2H), 4.53 (d, J=2.0 Hz, 1H), 4.45-4.38 (m, 2H), 4.38-4.29 (m, 2H),4.13 (q, J=7.0 Hz, 2H), 3.98 (dd, J=13.9, 1.3 Hz, 1H), 3.91 (s, 3H),2.61-2.53 (m, 1H), 1.97 (tt, J=8.4, 5.4 Hz, 1H), 1.15 (t, J=7.1 Hz, 3H),1.06 (s, 9H), 0.95-0.77 (m, 2H), 0.64-0.48 (m, 2H); MS (ESI+) m/z 587(M+H)⁺.

Example 139B ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 139A (375.4 mg, 0.641 mmol) was dissolved in ethyl acetate (3.2mL) and dichloromethane (3.2 mL) and was treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (207.7 mg, 1.330 mmol) andtetrakis(triphenylphosphine)palladium (7.9 mg, 6.84 μmol). The reactionmixture was stirred at ambient temperature. After 1 hour, the reactionmixture was diluted with methyl tert-butyl ether (50 mL) and stirredwith 15 mL of aqueous 10% Na₂CO₃ (50 mL) solution for 30 minutes. Thephases were then separated, and the organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography 5% to 10% ethyl acetate in dichloromethaneto provide the title compound (305.4 mg, 95%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 7.69-7.64 (m, 2H), 7.59-7.50 (m, 2H), 7.43 (s, 1H), 7.34(ddd, J=8.1, 7.0, 1.2 Hz, 1H), 7.18-7.10 (m, 2H), 7.01-6.94 (m, 1H),4.65 (d, J=4.3 Hz, 1H), 4.30 (dd, J=13.8, 1.3 Hz, 1H), 4.21-4.11 (m,3H), 3.93 (dd, J=13.8, 1.3 Hz, 1H), 3.90 (s, 3H), 3.66 (d, J=6.3 Hz,1H), 2.94 (s, 1H), 2.44 (dd, J=6.3, 1.6 Hz, 1H), 2.04-1.93 (m, 1H), 1.22(t, J=7.1 Hz, 3H), 1.01 (s, 9H), 0.92-0.80 (m, 2H), 0.66-0.51 (m, 2H);MS (ESI+) m/z 503 (M+H)⁺.

Example 139C ethyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

(S)-(−)-tetrahydro-2-furoic acid (44.3 mg, 0.382 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M in dichloromethane, 250 μL,0.50 mmol) was added followed by dimethylformamide (25 μL). The reactionmixture was stirred at room temperature for 3 hours, concentrated,redissolved in dichloromethane (1 mL), and concentrated again. Theresidue was taken up in dichloromethane (3×1 mL) and added to a solutionof Example 139B (140.0 mg, 0.279 mmol) and triethylamine (150 μL, 1.076mmol) in dichloromethane (3 mL). The reaction mixture was stirred atambient temperature for 17 hours. The mixture was diluted withdichloromethane (100 mL) and washed twice with saturated aqueous NaHCO₃and once with brine. The organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified by silica gel chromatography,eluting with 5% to 10% ethyl acetate in dichloromethane to provide thetitle compound (105.4 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm8.01 (d, J=6.0 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.57-7.47 (m, 2H),7.37-7.31 (m, 1H), 7.17 (d, J=10.4 Hz, 3H), 7.05-6.97 (m, 1H), 5.93 (s,1H), 4.78 (s, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.35 (dd, J=13.9, 1.2 Hz,1H), 4.16-4.06 (m, 2H), 3.99 (dd, J=14.0, 1.3 Hz, 1H), 3.91 (d, J=0.8Hz, 3H), 3.67 (dd, J=19.3, 12.3 Hz, 2H), 2.55 (s, 1H), 2.06-1.91 (m,2H), 1.86-1.55 (m, 4H), 1.14 (td, J=7.1, 0.9 Hz, 3H), 1.05 (d, J=0.8 Hz,9H), 0.87 (dtd, J=27.2, 9.1, 4.6 Hz, 2H), 0.64 (dq, J=9.5, 5.1 Hz, 1H),0.53 (dq, J=9.6, 5.1 Hz, 1H); MS (ESI+) m/z 601 (M+H)⁺.

Example 139D(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 139C (73.1 mg, 0.118 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 1.0 mL, 1.0 mmol) was addedand the reaction mixture was heated to 50° C. for 16 hours. The reactionmixture was concentrated, and 2 mL of water and 3 mL of dichloromethanewere added. The aqueous layer was acidified with 1 M aqueous HCl topH˜2, then diluted to 25 mL with water. The aqueous layer was extractedwith dichloromethane (2×25 mL). The combined organic layers were washedwith brine (25 mL), dried over Na₂SO₄, filtered and concentrated toprovide the title compound (97.3 mg, 100%). ¹H NMR (400 MHz, DMSO-d₆,120° C.) δ ppm 8.06 (d, J=7.1 Hz, 1H), 7.66 (dt, J=8.1, 1.0 Hz, 1H),7.57-7.46 (m, 2H), 7.34 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.17 (d, J=13.7Hz, 3H), 7.00 (dd, J=7.2, 2.1 Hz, 1H), 5.93 (s, 1H), 4.74 (d, J=1.7 Hz,1H), 4.42-4.34 (m, 2H), 4.21-4.03 (m, 1H), 3.99 (dd, J=14.0, 1.3 Hz,1H), 3.91 (d, J=0.8 Hz, 3H), 3.71 (t, J=7.3 Hz, 1H), 3.62 (d, J=7.6 Hz,1H), 2.61 (s, 1H), 2.48-2.47 (m, 1H), 2.07-1.89 (m, 2H), 1.87-1.73 (m,1H), 1.64 (s, 1H), 1.05 (d, J=0.9 Hz, 9H), 0.96-0.77 (m, 2H), 0.68-0.58(m, 1H), 0.52 (dtd, J=9.5, 5.4, 3.6 Hz, 1H); MS (ESI+) m/z 593 (M+H)⁺.

Example 140(2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 43A-Example 43B, substituting Example 117A for Example 40A, andcyclobutylzinc(II) bromide for cyclohexylzinc bromide in Example 43A. ¹HNMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.26 (s, 1H), 7.56(s, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.20-7.05 (m, 2H), 6.97 (d, J=7.7 Hz,1H), 5.36 (s, 1H), 4.58 (s, 1H), 4.31-4.23 (m, 2H), 4.19 (s, 1H), 3.86(s, 4H), 3.73 (q, J=7.3 Hz, 1H), 3.65 (d, J=20.0 Hz, 1H), 3.46-3.34 (m,1H), 2.27-2.15 (m, 2H), 1.99-1.85 (m, 3H), 1.76 (tdd, J=12.9, 8.0, 5.2Hz, 3H), 1.60 (s, 1H), 0.99 (s, 9H); MS (APCI+) m/z 605.2 (M+H)⁺.

Example 141(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 141A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

Tetrahydropyran-2-carboxylic acid (64.1 mg, 0.493 mmol) was dissolved indichloromethane (2 mL). Oxalyl chloride (2M in dichloromethane, 300 μL,0.60 mmol) was added followed by dimethylformamide (25 μL). The reactionwas stirred at ambient temperature for 3 hours, at which point it wasconcentrated, redissolved in dichloromethane (1 mL), and concentratedagain. The residue was taken up in dichloromethane (3×1 mL) and added toa solution of Example 129H (116 mg, 0.235 mmol) and triethylamine (130μL, 0.933 mmol) in dichloromethane (3 mL). The reaction was stirred atambient temperature for 17 hours. After this time, the mixture wasdiluted with dichloromethane (100 mL) and washed twice with saturatedaqueous NaHCO₃, and once with brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. The residue was purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A).The title compound was the second eluting diastereomer and was isolatedas the TFA salt (43.1 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm8.28 (s, 1H), 8.01-7.91 (m, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.13-6.91 (m,3H), 5.56 (s, 1H), 4.68 (s, 1H), 4.33-4.21 (m, 3H), 4.09 (qd, J=7.1, 2.8Hz, 2H), 3.86 (s, 3H), 3.82 (d, J=13.9 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H),2.90 (s, 1H), 2.42 (t, J=1.3 Hz, 1H), 2.34 (s, 3H), 1.77-1.22 (m, 6H),1.14 (t, J=7.0 Hz, 3H), 1.02 (s, 9H); MS (ESI+) m/z 607 (M+H)⁺.

Example 141B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 141A (40.7 mg, 0.056 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL), concentrated andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (27.0 mg, 69%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.31-8.24 (m, 1H), 8.08-7.99(m, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.11-6.98 (m, 3H), 5.56 (s, 1H), 4.64(s, 1H), 4.32-4.24 (m, 2H), 3.91-3.82 (m, 5H), 3.76 (d, J=11.3 Hz, 2H),2.50 (s, 1H), 2.33 (s, 3H), 1.74-1.23 (m, 6H), 1.02 (s, 9H); MS (ESI+)m/z 579 (M+H)⁺.

Example 142(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 142A 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-5-(3-chlorophenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 79C (40.0 mg, 0.097 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (35.0 mg, 0.137 mmol)were dissolved in dimethylformamide (1.1 mL). The reaction was cooled to0° C., and potassium tert-butoxide (1M in tetrahydrofuran, 0.12 mL, 0.12mmol) was added dropwise and the reaction was stirred at ambienttemperature for 1 hour. The reaction was quenched by the addition of 1Maqueous HCl (0.1 mL) and purified by reverse-phase preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm). Agradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B)was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0minutes linear gradient 95-10% A). The title compound was the secondeluting diastereomer and was isolated as the TFA salt (30.0 mg, 44%). ¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.81-7.77 (m, 1H), 7.67 (t, J=1.8Hz, 1H), 7.48 (dt, J=7.6, 1.5 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.19-7.14(m, 1H), 6.94 (d, J=2.4 Hz, 1H), 5.00 (d, J=6.1 Hz, 1H), 4.66 (p, J=6.2Hz, 1H), 4.35 (d, J=3.0 Hz, 1H), 4.28-4.19 (m, 2H), 4.10 (qd, J=7.1, 2.3Hz, 2H), 3.96-3.87 (m, 1H), 3.76 (s, 3H), 3.36 (p, J=8.4 Hz, 1H), 2.43(t, J=2.8 Hz, 1H), 2.32-2.19 (m, 2H), 2.04-1.78 (m, 4H), 1.16 (t, J=7.1Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.00 (s, 9H), 0.92 (d, J=6.2 Hz, 3H);MS (ESI+) m/z 587 (M+H)⁺.

Example 142B(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 142A (27.0 mg, 0.039 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 0.5 mL, 0.5 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (0.5 mL) and purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A).The title compound was the second eluting diastereomer and was isolatedas the TFA salt (30.0 mg, 44%)¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm7.79 (d, J=2.5 Hz, 1H), 7.70 (t, J=1.8 Hz, 1H), 7.50 (dt, J=7.3, 1.5 Hz,1H), 7.21 (t, J=7.7 Hz, 1H), 7.16 (dt, J=8.4, 1.5 Hz, 1H), 6.95-6.89 (m,1H), 4.99 (d, J=6.3 Hz, 1H), 4.65 (hept, J=6.2 Hz, 1H), 4.31 (d, J=3.0Hz, 1H), 4.27-4.20 (m, 2H), 3.92 (d, J=13.1 Hz, 1H), 3.77 (s, 3H), 3.35(p, J=8.3 Hz, 1H), 2.50 (s, 1H), 2.32-2.19 (m, 2H), 2.04-1.79 (m, 4H),1.06 (d, J=6.3 Hz, 3H), 0.99 (s, 9H), 0.92 (d, J=6.2 Hz, 3H); MS (ESI+)m/z 559 (M+H)⁺.

Example 143(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 92D to Example 92E, substituting Example 106B for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine in Example 92D. ¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.05-7.97 (m, 1H), 7.66 (dd,J=8.5, 1.4 Hz, 1H), 7.58-7.49 (m, 2H), 7.34 (ddd, J=8.0, 7.0, 1.2 Hz,1H), 7.22 (s, 1H), 7.12 (td, J=6.9, 6.1, 4.0 Hz, 2H), 6.98 (dd, J=6.4,2.5 Hz, 1H), 5.59 (d, J=5.7 Hz, 1H), 4.64 (hept, J=6.3 Hz, 1H), 4.44 (d,J=1.9 Hz, 1H), 4.39-4.30 (m, 2H), 3.98 (dd, J=14.1, 1.4 Hz, 1H), 3.91(s, 3H), 2.61-2.55 (m, 1H), 1.96 (tt, J=8.5, 5.4 Hz, 1H), 1.08-0.99 (m,12H), 0.95-0.77 (m, 5H), 0.58 (dtt, J=9.3, 7.1, 4.6 Hz, 2H); MS (ESI+)m/z 565 (M+H)⁺.

Example 144(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 144A (2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-1,2-dicarboxylate

To Core 10 (957 mg, 2.397 mmol) in toluene (10 mL) and saturated aqueousNaHCO₃ (10 mL) was added allyl carbonochloridate (0.3 mL, 2.82 mmol)dropwise at ambient temperature. The mixture was stirred at ambienttemperature overnight. The reaction was poured into water (50 mL) andextracted with dichloromethane (3×50 mL). The organic layer was washedwith brine and concentrated and purified by silica gel chromatographyusing a 40 g cartridge and eluting with 0->5% ethyl acetate indichloromethane to provide (2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-nitropyrrolidine-1,2-dicarboxylate(1.16 g, 2.400 mmol, 100% yield). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δppm 7.78 (dd, J=7.7, 1.5 Hz, 1H), 7.24-7.04 (m, 2H), 6.99 (dd, J=7.5,1.5 Hz, 1H), 6.00 (d, J=8.6 Hz, 1H), 5.67 (ddt, J=17.2, 10.5, 5.2 Hz,1H), 5.56 (dd, J=8.6, 2.5 Hz, 1H), 5.05-4.92 (m, 2H), 4.60 (d, J=3.4 Hz,1H), 4.41 (dq, J=4.8, 1.5 Hz, 2H), 4.31-4.21 (m, 2H), 3.06 (t, J=3.0 Hz,1H), 2.06 (tt, J=8.4, 5.4 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H), 1.04 (s, 9H),1.02-0.89 (m, 2H), 0.80 (dtd, J=9.4, 5.2, 3.4 Hz, 1H), 0.59-0.48 (m,1H).; MS (APCI+) m/z 483/485 (M+H)⁺ Br doublet.

Example 144B (2S,3R,5S)-1-allyl 2-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-oxopyrrolidine-1,2-dicarboxylate

To a solution of potassium dichromate (3.72 g, 12.65 mmol) in 6 Naqueous HCl (50 mL) was added zinc (4.41 g, 67.5 mmol) under N₂atmosphere. After the almost complete dissolution of zinc yielded aclear bright blue solution, the formed chromium(II) chloride wastransferred to the refluxing solution of Example 144A (1.14 g, 2.359mmol) in ethanol (25 mL) under N₂ using an addition funnel (internaltemp 78° C.). The reaction mixture was refluxed at 85° C. overnight andcooled and diluted with 300 mL of dichloromethane. The organic phase wasseparated, dried over sodium sulfate, filtered and concentrated. Thecrude material was then taken up in anhydrous ethanol and treated with asolution of HCl in ethanol (prepared by adding 2.0 mL of acetyl chlorideto an ice bath cooled solution of 6 mL of ethanol), and heated at 65° C.for one hour. The ethanol was removed and the crude material was dilutedwith 300 mL of methyl tert-butyl ether, washed with 50 mL each ofsaturated aqueous sodium bicarbonate and brine, and dried over sodiumsulfate. After filtration, the solvent was removed in vacuo to provide(2S,3R,5S)-1-allyl 2-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-oxopyrrolidine-1,2-dicarboxylate(1.067 g, 2.359 mmol, 100% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.81(dd, J=7.8, 1.7 Hz, 1H), 7.59 (dd, J=8.0, 1.3 Hz, 1H), 7.33 (td, J=7.6,1.3 Hz, 1H), 7.19 (ddd, J=8.0, 7.3, 1.7 Hz, 1H), 5.71 (ddt, J=16.9,11.0, 5.2 Hz, 1H), 5.45 (s, 1H), 5.10-4.99 (m, 2H), 4.64 (dd, J=4.6, 0.6Hz, 1H), 4.46 (dtd, J=5.2, 1.5, 0.7 Hz, 2H), 4.29-4.16 (m, 2H), 2.63(dd, J=4.6, 0.9 Hz, 1H), 1.30-1.22 (m, 3H), 1.06 (s, 9H); MS (APCI+) m/z452 (M+H)⁺.

Example 144C (2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 144B (850 mg, 1.879 mmol) was dissolved in ethanol (10 mL) andcooled in an ice/acetone bath. Sodium tetrahydroborate (85 mg, 2.255mmol) was added in small portions over 30 minutes. The reaction mixturewas concentrated in vacuo (no heat) and 10 mL of saturated aqueoussodium bicarbonate and 15 mL of ethyl acetate were added. The reactionmixture was stirred at room temperature for 30 minutes. The organicswere diluted with 50 mL more ethyl acetate, separated, washed withbrine, dried over sodium sulfate, filtered, and concentrated. The cruderesidue was loaded onto a 24 g silica gel column and eluted with 5-100%ethyl acetate/heptanes to provide a 0.584 g of a mixture ofdiastereomers. The crude material was rechromatographed using a 24 gsilica gel cartridge with a gradient of 5-30% ethyl acetate/heptanesover 20 minutes to provide (2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxypyrrolidine-1,2-dicarboxylate(0.465 g, 1.023 mmol, 54.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.93(dd, J=7.9, 1.7 Hz, 1H), 7.47 (dd, J=8.0, 1.2 Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 7.09 (td, J=7.7, 1.7 Hz, 1H), 5.69 (ddt, J=17.7, 10.1, 5.0 Hz,1H), 5.20 (d, J=6.0 Hz, 1H), 5.05-4.94 (m, 2H), 4.51-4.42 (m, 2H),4.41-4.33 (m, 3H), 4.20 (d, J=7.0 Hz, 2H), 2.29 (t, J=2.8 Hz, 1H), 1.25(t, J=7.1 Hz, 3H), 1.00 (s, 9H); MS (APCI+) m/z 454 (M+H)⁺.

Example 144D (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

Example 144C (0.465 g, 1.023 mmol) was dissolved in ethyl acetate (5 mL)and dichloromethane (5 mL), degassed with a stream of nitrogen bubblingthrough, and treated with 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(0.320 g, 2.047 mmol) and tetrakis(triphenylphosphine)palladium (0.008g, 6.92 μmol). The reaction stirred at room temperature. After 10minutes, the reaction was complete. To the reaction mixture was addedtriethylamine (0.856 mL, 6.14 mmol) followed by dropwise addition of(S)-tetrahydrofuran-2-carbonyl chloride (0.164 g, 1.219 mmol) as asolution in 0.2 mL of dichloromethane. The reaction mixture was quenchedwith 5 mL of saturated aqueous NaHCO₃ and concentrated. The phases wereseparated and the crude organics were purified twice using a 12 g silicagel cartridge with a gradient of 5-100% ethyl acetate/heptanes over 20minutes to provide (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate(0.392 g, 0.837 mmol, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.16(d, J=7.8 Hz, 0H), 7.99 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.5Hz, 1H), 7.12 (t, J=7.7 Hz, 1H), 5.50 (s, 1H), 4.58 (s, 1H), 4.50 (d,J=6.1 Hz, 1H), 4.17 (qd, J=7.1, 1.1 Hz, 2H), 3.70 (q, J=7.2 Hz, 1H),3.66-3.56 (m, 1H), 2.28 (t, J=2.7 Hz, 1H), 2.18 (d, J=6.6 Hz, 0H),2.02-1.83 (m, 1H), 1.77 (dp, J=14.0, 6.8, 6.3 Hz, 1H), 1.66 (s, 1H),1.33-1.18 (m, 3H), 0.99 (d, J=4.8 Hz, 10H), 0.85 (ddt, J=9.0, 6.3, 3.5Hz, 1H); (APCI+) m/z 468 (M+H)⁺.

Example 144E (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

Example 144D (108 mg, 0.231 mmol) was dried azeotropically three timeswith toluene, dissolved in dimethyl formamide (1 mL), and cooled to 0°C. Potassium 2-methylpropan-2-olate (1M in tetrahydrofuran, 0.277 mL,0.277 mmol) was added dropwise, followed by dropwise addition of3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (70.9 mg, 0.277 mmol).After 10 minutes, the reaction was quenched with 2 mL of saturatedaqueous NH₄Cl and the organics were taken up in dichloromethane andpurified using a 10 g silica gel cartridge, eluting with 5-100% ethylacetate-heptanes over 20 minutes to provide (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate(108 mg, 0.168 mmol, 72.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03(s, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.26 (t, J=7.3Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 5.60 (s, 1H),4.78 (s, 1H), 4.38 (d, J=5.8 Hz, 1H), 4.25 (s, 1H), 4.10 (q, J=7.1 Hz,2H), 3.92 (d, J=13.0 Hz, 1H), 3.86 (d, J=10.3 Hz, 1H), 3.75 (s, 3H),3.73-3.59 (m, 2H), 3.40-3.31 (m, 1H), 2.30-2.18 (m, 2H), 2.06-1.90 (m,3H), 1.90-1.73 (m, 2H), 1.69 (s, 1H), 1.32-1.23 (m, 1H), 1.14 (t, J=7.1Hz, 3H), 1.02 (s, 9H), 0.95 (s, 1H), 0.85 (tt, J=5.4, 2.6 Hz, 1H); MS(APCI+) m/z 643 (M+H)⁺.

Example 144F(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 144E (108 mg, 0.168 mmol) and lithium hydroxide (33.7 mg, 1.407mmol) were dissolved in methanol (0.5 mL), tetrahydrofuran (1 mL) andwater (1 mL). The reaction was warmed at 45° C. overnight. The solventswere removed under a stream of nitrogen. The residue was acidified with0.705 mL of 2N aqueous HCl and chromatographed using a 12 g silica gelcartridge with an ethanol/ethyl acetate/heptanes solvent system toprovide 127 mg of impure product. The material was purified again usingreverse phase HPLC method TFA8 to provide(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylicacid (68 mg, 0.110 mmol, 65.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.09 (s, 1H), 7.77 (dd, J=2.5, 0.7 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.26(t, J=7.6 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.87-6.82 (m, 1H), 5.60 (s,1H), 4.72 (s, 1H), 4.36 (d, J=6.0 Hz, 1H), 4.25 (dt, J=13.3, 0.8 Hz,1H), 3.94 (dt, J=13.3, 0.9 Hz, 1H), 3.76 (s, 3H), 3.76-3.67 (m, 1H),3.68-3.60 (m, 1H), 3.39-3.26 (m, 1H), 2.53 (s, 1H), 2.30-2.17 (m, 2H),2.03-1.87 (m, 5H), 1.91-1.69 (m, 2H), 1.74-1.62 (m, 2H), 1.01 (s, 9H);MS (APCI+) m/z 617 (M+H)⁺ (Br doublet).

Example 145(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 86 substituting Core 21 for Core 10 in Example 86A and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine for3-(bromomethyl)-5-trifluromethyl-2-methoxypyridine in Example 86D. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.72 (s, 1H), 8.40 (d, J=7.9 Hz, 1H), 7.75(d, J=2.4 Hz, 1H), 7.61 (dd, J=8.0, 1.2 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H),7.41 (t, J=7.6 Hz, 1H), 6.84 (s, 1H), 5.15 (d, J=5.3 Hz, 1H), 4.51 (s,1H), 4.35 (d, J=1.4 Hz, 1H), 4.21 (d, J=13.7 Hz, 1H), 4.05 (d, J=5.4 Hz,1H), 3.83 (d, J=13.7 Hz, 1H), 3.68 (s, 3H), 2.23-2.10 (m, 2H), 1.98-1.76(m, 4H), 1.18-1.04 (m, 2H), 0.96 (s, 9H), 0.89 (bs, 2H), 0.51 (bs, 2H);MS (ESI+) m/z 593 (M+H)⁺.

Example 146(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 146A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

To Example 133D (244 mg, 0.562 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (182 mg, 0.674mmol) in dimethylformamide (2 mL) while cooling in an ice bath,potassium 2-methylpropan-2-olate (82 mg, 0.730 mmol, 0.73 mL, 1.0 M intetrahydrofuran) was added dropwise. The mixture was stirred in ice-bathfor 30 minutes, and was allowed to warm to room temperature.Dichloromethane and saturated aqueous NH₄Cl were added. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography, eluting withethyl acetate in heptanes at a 0-40% gradient to provide the titlecompound (260 mg, 74.2% yield). LC/MS (APCI+) m/z 624.24 (M+H)⁺.

Example 146B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

To a solution of Example 146A (250 mg, 0.401 mmol) and diethylamine(0.083 mL, 0.802 mmol) in acetonitrile/water (8.8 mL, 10:1) was addedtetrakis(triphenylphosphine)palladium(0) (10.19 mg, 8.82 μmol). Themixture was stirred at ambient temperature overnight, and LC/MS showedthe conversion was complete. Dichloromethane (20 mL) and water (10 mL)were added, and the organic layer was washed with brine, dried overMgSO₄, filtered, and concentrated to provide the title compound 200 mg(92% yield) which used in the next step without further purification.LC/MS (APCI+) m/z 540.32 (M+H)⁺.

Example 146C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

To (S)-tetrahydrofuran-2-carboxylic acid (34.4 mg, 0.297 mmol) and adrop of dimethylformamide in dichloromethane (2 mL) was added oxalyldichloride (56.5 mg, 0.445 mmol, 0.23 mL, 2M in dichloromethane). Themixture was stirred at ambient temperature for 30 minutes. The solventwas removed under pressure and fresh dichloromethane was added andremoved again. The residue in dichloromethane (1 mL) was added dropwiseto a solution of Example 146B (80 mg, 0.148 mmol) and triethylamine(0.083 mL, 0.593 mmol) in dichloromethane (6 mL) in an ice-bath. Themixture was stirred in an ice-bath for 30 minutes, and then at ambienttemperature for 30 minutes. Dichloromethane and saturated aqueous NH₄Clwere added and the organic layer washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by chromatography,eluting with ethyl acetate in heptanes at 0-40% gradient to provide thetitle compound.

Example 146D(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

Example 146C was dissolved in methanol (1.5 mL) and aqueous LiOH (6M,0.5 mL). The mixture was stirred at 45° C. overnight. LC/MS indicatedthe conversion was finished, and the mixture was adjusted pH to 1˜2 byadding 2M aqueous HCl. The resulting mixture was purified via silica gelchromatography, eluting with methanol in dichloromethane using agradient of 0-20% to provide title compound 36 mg (39.8% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.57-8.26 (m, 2H), 7.90 (s, 1H), 7.08-7.00 (m,1H), 6.77 (s, 1H), 5.60 (s, 2H), 5.20 (p, J=6.2 Hz, 1H), 4.48 (s, 1H),4.40 (d, J=14.0 Hz, 1H), 4.26 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.89 (s,3H), 3.78 (s, 1H), 3.66 (s, 1H), 2.64 (d, J=4.6 Hz, 1H), 1.77 (d, J=64.0Hz, 4H), 1.28 (dd, J=6.1, 4.4 Hz, 3H), 1.16 (d, J=6.1 Hz, 3H), 1.01 (d,J=4.9 Hz, 9H); MS (ESI+) m/z 610 (M+H)⁺.

Example 147(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 146C-146D substituting isopropyl carbonochloridate for(S)-tetrahydrofuran-2-carboxylic acid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.29 (d, J=9.2 Hz, 2H), 7.87 (dd, J=4.9, 1.9 Hz, 1H), 7.09 (d, J=2.4 Hz,1H), 6.75 (dd, J=7.4, 4.9 Hz, 1H), 5.25-5.16 (m, 2H), 4.67 (dq, J=12.4,6.2 Hz, 1H), 4.37 (d, J=14.0 Hz, 1H), 4.32 (d, J=2.7 Hz, 1H), 4.23 (dd,J=6.2, 1.8 Hz, 1H), 4.00 (d, J=14.0 Hz, 1H), 3.88 (s, 3H), 2.54 (t,J=2.2 Hz, 1H), 1.28 (d, J=6.1 Hz, 3H), 1.18 (d, J=6.1 Hz, 3H), 1.06 (d,J=6.2 Hz, 3H), 1.00 (s, 9H), 0.91 (d, J=6.2 Hz, 3H); MS (ESI+) m/z(M+H)⁺.

Example 148(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 112A-112G, substituting Core 19 for Core 12 in Example 112A, andsubstituting 3-(bromomethyl)-2-methoxyquinoline (Example 106B) for3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine in Example 112D.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.69 (d, J=8.4 Hz, 1H), 7.65(dd, J=8.0, 1.4 Hz, 1H), 7.55 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.44 (s,1H), 7.35 (ddd, J=8.1, 6.8, 1.2 Hz, 2H), 6.62 (s, 1H), 5.59 (s, 1H),4.72 (p, J=6.4 Hz, 1H), 4.65 (s, 1H), 4.43 (dd, J=14.0, 1.2 Hz, 1H),4.37 (s, 1H), 4.22 (s, 1H), 4.10 (d, J=13.9 Hz, 1H), 3.95 (d, J=0.8 Hz,3H), 3.69 (dt, J=13.7, 6.9 Hz, 2H), 2.61 (s, 1H), 2.06 (q, J=5.6 Hz,1H), 1.88-1.65 (m, 3H), 1.39 (d, J=6.3 Hz, 3H), 1.28 (d, J=6.5 Hz, 3H),1.02 (s, 9H); MS (ESI+) m/z 565 (M+H)⁺.

Example 149(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 149A (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

Pyridinium dichromate (8.72 g, 23.17 mmol) in 6N aqueous HCl (200 mL)was cooled to 0° C. and treated with zinc dust (16.66 g, 255 mmol) inportions over about 20 minutes. After completion of the addition, themixture was brought to room temperature and stirred until all zincdissolved and bubbling stopped (˜2 h). The deep blue solution was thentransferred via cannula to a refluxing solution of Example 112A (4.12 g,9.27 mmol) in ethanol (100 mL) over about 35 minutes. The reactionmixture was heated at strong reflux (heating block temp: 98° C.)overnight. After this time, heating was discontinued, and the mixturewas transferred to a separatory funnel and extracted three times withdichloromethane (100 mL each). The combined organics were then driedover Na₂SO₄, filtered and concentrated in vacuo, and the crude residuewas taken up in 28 mL ethanol and treated with a prepared solution of5.8 mL of acetyl chloride in 17 mL ethanol (solution prepared at 0° C.).The reaction mixture was refluxed for 1 hour, then was cooled to roomtemperature and concentrated in vacuo. Silica gel chromatography,eluting with 0 to 20% ethyl acetate-heptanes, provided the titlecompound, 1.566 g (41% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.69 (dd,J=6.8, 1.9 Hz, 1H), 7.11 (m, 3H), 5.73-5.63 (m, 2H), 5.06-4.94 (m, 2H),4.65 (d, J=5.0 Hz, 1H), 4.44 (d, J=5.3 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H),2.64 (d, J=5.0 Hz, 1H), 2.13 (tt, J=8.5, 5.4 Hz, 1H), 1.26 (t, J=7.1 Hz,3H), 1.07 (s, 9H), 0.97-0.73 (m, 3H), 0.52 (m, 1H); MS (ESI⁺) m/z 414.1(M+H)⁺.

Example 149B (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 149A (1.566 g, 3.79 mmol) in ethanol (15.5 mL) was cooled to−10° C. and the solution was treated in one portion with sodiumborohydride (0.233 g, 6.15 mmol). The reaction mixture was stirred inthe cold bath for a few minutes, then removed from the cold bath andallowed to warm to room temperature (˜40 minutes). After this time, themixture was concentrated in vacuo, and the residue was taken up in ethylacetate (50 mL) and saturated aqueous NaHCO₃ solution (50 mL), and themixture was stirred for 30 minutes. The mixture was transferred to aseparatory funnel, and the phases were separated. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo, and the crudematerial was purified by silica gel chromatography, eluting with 0 to30% ethyl acetate-heptanes to provide the title compound, 700 mg (45%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.91-7.82 (m, 1H), 7.12-7.03 (m,2H), 7.03-6.95 (m, 1H), 5.64 (m, 1H), 5.51 (d, J=6.3 Hz, 1H), 5.03-4.90(m, 2H), 4.45 (dd, J=6.2, 2.9 Hz, 1H), 4.36 (dt, J=6.1, 2.6 Hz, 3H),4.18 (q, J=7.0 Hz, 2H), 3.72 (m, 1H), 2.31 (t, J=3.3 Hz, 1H), 1.96 (tt,J=8.4, 5.4 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.00 (s, 9H), 0.96-0.79 (m,2H), 0.73 (dtd, J=9.4, 5.4, 3.6 Hz, 1H), 0.55 (dtd, J=8.4, 5.4, 3.3 Hz,1H); MS (ESI⁺) m/z 416.1 (M+H)⁺.

Example 149C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 149B (0.350 g, 0.842 mmol), dried azeotropically with toluene,was dissolved in dimethylformamide (8.4 mL) and the mixture was cooledto 0° C. Potassium 2-methylpropan-2-olate (1M in tetrahydrofuran, 0.93mL, 0.930 mmol) was added dropwise, followed by dropwise addition ofExample 130C (0.259 g, 1.011 mmol). The reaction mixture was stirred at0° C. for 45 minutes, poured into saturated aqueous NH₄Cl and extractedthree times with methyl tert-butyl ether. The combined organics weredried over Na₂SO₄, filtered, and concentrated in vacuo. Silica gelchromatography, eluting with 0 to 30% methyl tert-butyl ether-heptanes,provided the title compound, 0.353 g (71% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.90 (m, 1H), 7.75 (m, 1H), 7.14-7.02 (m, 2H), 6.96 (m,1H), 6.92-6.78 (m, 1H), 5.79-5.51 (m, 2H), 5.08-4.88 (m, 2H), 4.50 (d,J=2.0 Hz, 1H), 4.39 (dq, J=4.7, 1.5 Hz, 2H), 4.29 (dd, J=5.7, 1.1 Hz,1H), 4.24-4.01 (m, 3H), 3.81 (dt, J=13.1, 0.9 Hz, 1H), 3.74 (s, 3H),3.31 (m, 1H), 2.51 (m, 1H), 2.31-2.11 (m, 2H), 2.08-1.75 (m, 5H), 1.14(t, J=7.1 Hz, 3H), 1.03 (s, 9H), 0.95-0.78 (m, 2H), 0.65-0.52 (m, 2H);MS (ESI⁺) m/z 591.2 (M+H)⁺.

Example 149D (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylate

Example 149C (0.353 g, 0.598 mmol) was dissolved in ethyl acetate (3 mL)and dichloromethane (3 mL), and the solution was treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.187 g, 1.195 mmol) andtetrakistriphenylphosphine palladium (6.9 mg, 5.98 μmol). The reactionmixture was stirred at room temperature for 30 minutes, and was dilutedwith 20 mL methyl tert-butyl ether and stirred vigorously with 20 mL of10% aqueous Na₂CO₃ solution for 15 minutes. The phases were separated,and the organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was used directly intothe next reaction without further purification. MS (ESI⁺) m/z 507.2(M+H)⁺.

Example 149E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

(S)-Tetrahydrofuran-2-carboxylic acid (0.069 g, 0.598 mmol) was refluxedin thionyl chloride (0.57 mL, 7.77 mmol) for 1 hour. The mixture wascooled to room temperature and concentrated in vacuo. Excess thionylchloride was chased three times with dichloromethane (1 mL each), andthe resulting crude acid chloride was treated with a solution of Example149D (0.151 g, 0.299 mmol) in dichloromethane (1.4 mL) and with pyridine(0.29 mL, 3.59 mmol). The reaction was stirred at room temperature.After 1 hour, the reaction mixture was diluted with ethyl acetate (10mL) and washed with water (3×3 mL) and with brine (3 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was taken directly into the next reaction without furtherpurification. MS (APCI⁺) m/z 605.7 (M+H)⁺.

Example 149F(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 149E (0.181 g, 0.299 mmol) and lithium hydroxide (1M aqueous, 3mL, 3 mmol) were stirred in tetrahydrofuran (3 mL) and methanol (3 mL)at 45° C. overnight. The reaction mixture was cooled to room temperatureand acidified to pH 2 with 1N aqueous HCl. The mixture was concentratedin vacuo, and excess moisture was removed azeotropically withacetonitrile. The residue was chromatographed on silica gel, elutingwith 0 to 5% methanol-ethyl acetate, to obtain the still-impure product.The crude material was further purified by silica gel chromatography,eluting with 5 to 25% 3:1 ethyl acetate-ethanol/heptanes, to provide thetitle compound, 0.0235 g (14% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.02 (d, J=7.0 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.12 (m, 2H), 7.02-6.95(m, 1H), 6.82 (d, J=2.3 Hz, 1H), 5.89 (m, 1H), 4.69 (d, J=1.7 Hz, 1H),4.32 (d, J=5.8 Hz, 1H), 4.22 (d, J=13.3 Hz, 1H), 4.05 (m, 1H), 3.85 (d,J=13.5 Hz, 1H), 3.75 (s, 3H), 3.70 (m, 1H), 3.61 (m, 1H), 3.30 (p, J=8.5Hz, 1H), 2.55 (m, 1H), 2.27-2.17 (m, 2H), 2.01-1.80 (m, 7H), 1.63 (m,1H), 1.02 (s, 9H), 0.96-0.81 (m, 3H), 0.69-0.51 (m, 2H); MS (ESI⁺) m/z577.2 (M+H)⁺.

Example 150(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(oxane-4-carbonyl)pyrrolidine-2-carboxylicacid Example 150A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)-1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example149E, substituting tetrahydro-2H-pyran-4-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid. The crude product was takendirectly into the following reaction without further purification. MS(APCI⁺) m/z 619.7 (M+H)⁺.

Example 150B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(oxane-4-carbonyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure of Example149F, substituting Example 150A for Example 149E. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.00 (m, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.10 (m, 2H), 6.99(dd, J=7.2, 1.7 Hz, 1H), 6.86-6.80 (m, 1H), 5.68 (d, J=5.8 Hz, 1H), 4.64(d, J=1.8 Hz, 1H), 4.34 (d, J=5.8 Hz, 1H), 4.23 (d, J=13.3 Hz, 1H),3.89-3.80 (m, 2H), 3.75 (s, 3H), 3.65 (m, 1H), 3.31 (m, 1H), 3.11 (m,2H), 2.83 (m, 2H), 2.57 (m, 1H), 2.26-2.17 (m, 2H), 2.07-1.80 (m, 4H),1.52 (m, 4H), 1.02 (s, 9H), 0.97 (m, 1H), 0.90 (m, 1H), 0.67 (m, 1H),0.58 (m, 1H); MS (ESI⁺) m/z 591.4 (M+H)⁺.

Example 151(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 144 substituting 3-(bromomethyl)-2-methoxyquinoline (Example106B) for 3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine in Example144E. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.14 (s, 1H), 7.67 (d,J=8.5 Hz, 1H), 7.55 (dd, J=8.0, 6.1 Hz, 2H), 7.49 (d, J=7.9 Hz, 1H),7.39-7.24 (m, 3H), 7.15 (t, J=7.7 Hz, 1H), 5.64 (s, 1H), 4.76 (s, 1H),4.48-4.37 (m, 2H), 4.07 (d, J=13.8 Hz, 1H), 3.96-3.88 (m, 4H), 3.76-3.61(m, 2H), 2.60 (s, 1H), 2.05-1.91 (m, 1H), 1.89-1.59 (m, 3H), 1.04 (s,9H); MS (ESI+) m/z 5611 & 613 (M+H)⁺.

Example 152(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-1-(ethoxycarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid

Example 121F (50 mg, 0.093 mmol, 1.0 eq) and trimethylamine (39.2 μL,0.279 mmol, 3.0 eq) were dissolved in dichloromethane (1 mL). Ethylchloroformate (12.1 mg, 0.11 mmol, 1.3 eq) was added neat. The reactionwas stirred for 2 hours at room temperature. The reaction wasconcentrated and the residue was dissolved in 3:2tetrahydrofuran/methanol (1 mL). Aqueous LiOH (5 M, 300 uL) was addedand the reaction was stirred at 45° C. overnight. The solvent wasremoved under a stream of nitrogen, and the residue was acidified with 2M aqueous HCl and diluted with CH₃CN. Purification was carried out usingpreparative reverse phase HPLC MS method TFA 8 (37.5 mg, 58% yield). ¹HNMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.28-8.22 (m, 1H),7.73-7.60 (m, 1H), 7.38-7.28 (m, 1H), 7.17-7.03 (m, 3H), 5.02 (d, J=6.4Hz, 1H), 4.31 (d, J=3.4 Hz, 1H), 4.27-4.18 (m, 2H), 3.96-3.80 (m, 6H),2.47 (s, 1H), 1.17 (s, 9H), 0.99 (s, 9H), 0.94 (t, J=7.0 Hz, 3H); MS(APCI+) m/z 581.1 (M+H)⁺.

Example 153(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 153 was prepared using the procedure from Example 152,substituting isopropyl chloroformate for ethyl chloroformate. ¹H NMR(400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.25 (s, 1H), 7.66 (d,J=2.0 Hz, 1H), 7.34 (dt, J=6.9, 1.8 Hz, 1H), 7.16 (s, 1H), 7.14-7.03 (m,2H), 4.98 (d, J=6.3 Hz, 1H), 4.70-4.55 (m, 1H), 4.30 (d, J=3.4 Hz, 1H),4.26-4.18 (m, 2H), 3.88-3.82 (m, 4H), 2.50-2.44 (m, 1H), 1.17 (s, 9H),1.04 (d, J=6.2 Hz, 3H), 0.99 (s, 9H), 0.85 (d, J=6.3 Hz, 3H); MS (APCI+)m/z 595.1 (M+H)⁺.

Example 154(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptane-2-carbonyl]pyrrolidine-2-carboxylicacid

(1R,2S,4S)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (15.9 mg, 0.11mmol, 1.2 eq) was dissolved in dichloromethane (500 μL). Ghosez reagent(1-chloro-N,N,2-trimethyl-1-propenylamine) (25 μL, 0.25 mmol, 2.0 eq)was added neat and the reaction was stirred at room temperature for 10minutes. Example 121F (50 mg, 0.093 mmol, 1.0 eq) in 1:1tetrahydrofuran/pyridine (500 μL) was added and the reaction was stirredfor 2 hours at room temperature. The solvent was removed under a streamof nitrogen and the residue was dissolved in 3:2tetrahydrofuran/methanol (1 mL). Aqueous LiOH monohydrate (5 M, 300 uL)was added and the reaction was stirred at 45° C. overnight. The solventwas removed under a stream of nitrogen. The residue was acidified with 2M aqueous HCl and diluted with CH₃CN. Purification was carried out usingpreparative reverse phase HPLC MS method TFA 8 (37.5 mg, 58% yield). ¹HNMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.26 (s, 1H),7.89-7.68 (m, 1H), 7.50-7.39 (m, 1H), 7.20-7.09 (m, 3H), 5.21 (d, J=6.6Hz, 1H), 4.53-4.44 (m, 2H), 4.42-4.33 (m, 1H), 4.29-4.20 (m, 2H),4.01-3.83 (m, 4H), 2.44 (s, 1H), 1.86-1.66 (m, 1H), 1.60-1.31 (m, 2H),1.20-1.13 (m, 11H), 1.03-0.95 (m, 10H); MS (APCI+) m/z 633.1 (M+H)⁺.

Example 155(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 144 substituting Core 21 for Core 10. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.46 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.49(d, J=7.9 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 6.82 (s, 1H), 5.54 (s, 1H),4.69 (s, 1H), 4.19 (d, J=13.3 Hz, 1H), 4.13 (d, J=5.5 Hz, 1H), 3.82 (d,J=13.2 Hz, 1H), 3.73 (d, J=1.3 Hz, 4H), 3.63 (s, 1H), 3.31 (t, J=8.2 Hz,1H), 2.57 (s, 1H), 2.24 (d, J=8.2 Hz, 2H), 2.01-1.83 (m, 6H), 1.83-1.74(m, 1H), 1.68 (s, 1H), 1.00 (d, J=1.2 Hz, 9H); MS (APCI+) m/z 605(M+H)⁺.

Example 156(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 144 substituting Core 21 for Core 10 and3-(bromomethyl)-5-trifluromethyl-2-methoxypyridine for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.49 (d, J=8.1 Hz, 1H), 8.28 (s, 1H), 7.57 (d, J=7.9 Hz,1H), 7.45 (m, 1H), 7.35 (m, 1H), 7.06 (s, 1H), 5.55 (s, 1H), 4.66 (s,1H), 4.31 (d, J=13.9 Hz, 1H), 4.14 (s, 1H), 3.89 (d, J=14.0 Hz, 1H),3.85 (s, 3H), 3.73 (d, J=7.1 Hz, 1H), 3.63 (s, 1H), 2.62 (s, 1H), 1.90(s, 1H), 1.84-1.74 (m, 1H), 1.68 (s, 1H), 1.01 (s, 9H); MS (ESI+) m/z619 (M+H)⁺.

Example 157(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 157A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((R)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylateand Example 157B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-(tert-butyl)phenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

Into a 4 mL vial was added tetrahydro-2H-pyran-2-carboxylic acid (24.25mg, 0.186 mmol) and Ghosez reagent (37.0 μL, 0.280 mmol) indichloromethane (0.5 mL) to provide a colorless solution. The reactionwas stirred at room temperature for 10 minutes. Example 121F (50 mg,0.093 mmol) in 1 mL 1:1 tetrahydrofuran/pyridine was added. The reactionimmediately turned yellow. The reaction was stirred for 1 hour at roomtemperature. The solvent was removed under a stream of nitrogen. Theresidue was reconstituted in DMSO/methanol and purified on reverse phaseHPLC using HPLC method TFA8. Two diastereomers were isolated.

Example 157C(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 157A, the first eluting fraction, was diluted with 1 mL 3:2tetrahydrofuran/methanol and 5 M aqueous LiOH (300 uL) and heated to 45°C. overnight. The solvent was removed under a stream of nitrogen. Theresidue was acidified with 2 M aqueous HCl, and extracted withdichloromethane (3×1 mL). The solvent was removed under N₂ and residuewas dissolved in CH₃CN. Purification was carried out using preparativereverse phase HPLC MS method TFA 8 (22.5 mg, 39% yield). Thestereochemistry of the title compound was arbitrarily assigned. ¹H NMR(400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.25 (s, 1H), 7.64 (s,1H), 7.32 (s, 1H), 7.15-7.06 (m, 3H), 5.19 (d, J=6.2 Hz, 1H), 4.94-4.51(m, 1H), 4.37-4.16 (m, 2H), 3.98-3.59 (m, 6H), 2.54 (s, 1H), 1.87-1.70(m, 1H), 1.65-1.23 (m, 6H), 1.16 (s, 9H), 1.00 (s, 9H); MS (APCI+) m/z621.3 (M+H)⁺.

Example 158(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was synthesized according to the procedure describedin Example 157C, substituting Example 157B (second eluting isomer) forExample 157A. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm8.25 (d, J=2.2 Hz, 1H), 7.74 (s, 1H), 7.42 (d, J=7.0 Hz, 1H), 7.15 (d,J=7.7 Hz, 3H), 5.39 (s, 1H), 4.54 (s, 1H), 4.29-4.19 (m, 2H), 3.85 (s,5H), 3.59 (s, 1H), 2.44 (t, J=3.0 Hz, 1H), 1.69-1.25 (m, 7H), 1.17 (s,9H), 0.99 (s, 9H); MS (APCI+) m/z 621.3 (M+H)⁺.

Example 159(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 159A ethyl(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

Example 144D (96.4 mg, 0.206 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (80.0 mg, 0.296mmol) were dissolved in dimethylformamide (1 mL). The reaction wascooled to 0° C., potassium tert-butoxide (1M in tetrahydrofuran, 0.30mL, 0.30 mmol) was added dropwise and the reaction was stirred atambient temperature for 1 hour. The reaction was quenched by theaddition of 1M aqueous HCl (0.3 mL) and was purified by silica gelchromatography (0 to 5% ethyl acetate in dichloromethane) to provide thetitle compound (81.5 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm8.30 (s, 1H), 8.00 (s, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.23 (t, J=7.5 Hz,1H), 7.16-7.04 (m, 2H), 5.61 (d, J=1.2 Hz, 1H), 4.79 (s, 1H), 4.42 (d,J=5.8 Hz, 1H), 4.33 (d, J=13.6 Hz, 1H), 4.10 (qd, J=7.1, 1.4 Hz, 2H),4.01-3.92 (m, 2H), 3.87 (s, 3H), 3.77-3.55 (m, 2H), 2.49 (s, 1H),2.06-1.91 (m, 1H), 1.86-1.61 (m, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.03 (s,9H); MS (ESI+) m/z 657 & 659 (M+H)⁺.

Example 159B(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 159A (67.0 mg, 0.102 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 1.0 mL, 1.0 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasquenched by the addition of 1M aqueous HCl (1 mL), concentrated andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound (57.8 mg, 76%) as the TFA salt.¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.29 (s, 1H), 8.08 (s, 1H),7.45 (d, J=7.9 Hz, 1H), 7.22 (t, J=7.4 Hz, 1H), 7.14-7.02 (m, 2H), 5.62(s, 1H), 4.74 (s, 1H), 4.40 (d, J=6.1 Hz, 1H), 4.36 (d, J=13.8 Hz, 1H),4.01-3.94 (m, 2H), 3.88 (s, 3H), 3.78-3.61 (m, 2H), 2.55 (s, 1H),2.02-1.88 (m, 1H), 1.86-1.58 (m, 3H), 1.03 (s, 9H); MS (ESI+) m/z 629 &631 (M+H)⁺.

Example 160(2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was synthesized according to the procedure describedin Example 146A-146D, substituting Example 133E for Example 133D inExample 146A, and cyclobutanecarboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid in Example 146C. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.29 (s, 1H), 8.07 (s, 1H), 7.91 (d, J=4.8 Hz, 1H), 7.08(s, 1H), 6.78 (t, J=6.2 Hz, 1H), 5.26 (dd, J=11.0, 6.0 Hz, 2H), 4.50 (s,1H), 4.38 (d, J=13.7 Hz, 1H), 4.29 (dd, J=6.1, 2.0 Hz, 1H), 4.04-3.97(m, 1H), 3.88 (d, J=0.8 Hz, 3H), 2.52 (s, 1H), 2.21-1.96 (m, 5H), 1.72(s, 2H), 1.32 (d, J=6.1 Hz, 3H), 1.20 (d, J=6.1 Hz, 3H), 1.00 (s, 9H);MS (ESI+) m/z 594.1 (M+H)⁺.

Example 161 (2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutaecarbonyl)-4-[(5cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 161A (2S,3R,4R,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

The title compound was synthesized according to the procedure describedin Example 133F, substituting Example 133E for Example 133D.

Example 161B (2S,3R,4R,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate

The title compound was synthesized according to the procedure describedin Example 133G, substituting Example 161A for Example 133F.

Example 161C(2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 121G, substituting Example 161B for Example 121F, andcyclobutanecarboxylic acid for (S)-tetrahydrofuran-2-carboxylic acid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.08 (s, 1H), 7.96 (d, J=4.8 Hz, 1H), 7.76(d, J=2.5 Hz, 1H), 6.82 (dd, J=10.5, 4.2 Hz, 2H), 5.27 (dd, J=8.8, 6.2Hz, 2H), 4.47 (d, J=13.9 Hz, 1H), 4.29 (d, J=13.1 Hz, 1H), 4.24 (dd,J=6.2, 2.1 Hz, 1H), 3.96 (d, J=13.2 Hz, 1H), 3.76 (s, 3H), 3.33 (q,J=8.4 Hz, 1H), 3.27 (s, 1H), 3.2 (m, 1H), 3.03 (m, 1H), 2.30-1.80 (m,12H), 1.32 (d, J=6.1 Hz, 3H), 1.21 (d, J=6.1 Hz, 3H), 0.98 (s, 9H); MS(ESI+) m/z 580.2 (M+H)⁺.

Example 162(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 162A (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

Example 144D (68 mg, 0.145 mmol) and2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (49 mg, 0.191 mmol) weredried azeotropically with toluene, then dissolved in dimethylformamide(1 mL) and cooled to 0° C. Potassium 2-methylpropan-2-olate (1M intetrahydrofuran, 0.174 mL, 0.174 mmol) was added dropwise. After 15minutes, the reaction was quenched with 2 mL of saturated aqueous NH₄Cland 10 drops of HCl. The organics were taken up in dichloromethane andpurified using a 10 g silica gel cartridge, eluting with 5-100% methyltert-butyl ether-heptanes over 20 minutes to provide (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate(89 mg, 0.138 mmol, 95% yield). MS (APCI+) m/z 644 (M+H)⁺.

Example 162B(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 144D (89 mg, 0.138 mmol) and lithium hydroxide (0.552 mL, 1.104mmol) were dissolved in methanol (0.5 mL), tetrahydrofuran (1 mL) andwater (1 mL). The reaction was warmed at 45° C. overnight. The solventwas removed under a stream of nitrogen and acidified with 0.552 mL of 2Naqueous HCl. The crude material was chromatographed using a 12 g silicagel cartridge with an ethanol/ethyl acetate/heptanes solvent system toprovide(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylicacid (39 mg, 0.063 mmol, 45.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.12 (d, J=7.7 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.24 (t, J=7.7 Hz, 1H),7.11 (dd, J=8.6, 2.7 Hz, 2H), 6.83 (d, J=2.6 Hz, 1H), 6.73 (d, J=8.6 Hz,1H), 5.58 (s, 1H), 4.66 (s, 1H), 4.33 (d, J=6.1 Hz, 1H), 4.21 (d, J=12.4Hz, 1H), 3.92 (d, J=12.4 Hz, 1H), 3.76-3.69 (m, 1H), 3.63 (s, 3H), 2.52(s, 1H), 1.95 (s, 1H), 1.80 (dt, J=13.5, 6.5 Hz, 1H), 1.68 (s, 1H), 1.25(d, J=1.8 Hz, 1H), 1.17 (s, 9H), 0.98 (s, 9H), 0.91-0.78 (m, 1H); MS(APCI+) m/z 615/617 (M+H)⁺ (Br doublet).

Example 163(2S,3R,4R,5S)-3-tert-butyl-1-(cyclopentanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was synthesized according to the procedure describedin Example 146A-146D, substituting Example 133E for Example 133D inExample 146A, and cyclopentanecarboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid in Example 146C. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.51-8.33 (m, 2H), 8.11-8.05 (m, 1H), 7.90 (d, J=2.4 Hz,1H), 6.96 (t, J=6.2 Hz, 1H), 5.53-5.45 (m, 1H), 5.24 (s, 1H), 4.99 (d,J=13.4 Hz, 1H), 4.64 (d, J=13.3 Hz, 1H), 4.38 (d, J=11.3 Hz, 1H), 4.04(d, J=3.6 Hz, 1H), 4.01 (d, J=1.1 Hz, 3H), 2.34 (s, 1H), 2.11 (d, J=11.5Hz, 1H), 1.68 (dd, J=11.5, 8.1 Hz, 1H), 1.55 (s, 4H), 1.42 (d, J=6.2 Hz,3H), 1.36 (s, 1H), 1.34 (d, J=6.1 Hz, 3H), 1.00 (d, J=1.1 Hz, 9H); MS(ESI+) m/z 608.1 (M+H)⁺.

Example 164(2S,3R,4R,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was synthesized according to the procedure describedin Example 146A-146D, substituting Example 133E for Example 133D inExample 146A, and cyclohexanecarboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid in Example 146C. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.48 8.45 (m, 1H), 8.41 (s, 1H), 8.09 (d, J=4.7 Hz, 1H),7.88 (d, J=2.4 Hz, 1H), 6.96 (t, J=6.2 Hz, 1H), 5.51 (p, J=6.1 Hz, 1H),5.19 (s, 1H), 4.98 (d, J=13.3 Hz, 1H), 4.63 (d, J=13.3 Hz, 1H), 4.36 (d,J=11.4 Hz, 1H), 4.02 (d, J=3.6 Hz, 1H), 4.00 (s, 3H), 2.13 (dd, J=11.4,3.6 Hz, 1H), 1.68-1.45 (m, 4H), 1.42 (d, J=6.2 Hz, 3H), 1.35 (d, J=6.2Hz, 3H), 1.33-1.02 (m, 6H), 1.00 (s, 9H); MS (ESI+) m/z 622.1 (M+H)⁺.

Example 165(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-[2-(difluoromethyl)phenyl]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedures described inExample 144 substituting Core 22 for Core 10. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.33 (d, J=7.8 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.48 (d, J=7.6 Hz,1H), 7.42-7.29 (m, 2H), 7.34 (t, J=55.0 Hz, 1H), 6.80 (s, 1H), 5.54 (s,1H), 4.58 (s, 1H), 4.21-4.12 (m, 2H), 3.79 (d, J=13.3 Hz, 1H), 3.74 (m,4H), 3.62 (s, 1H), 3.30 (p, J=8.4 Hz, 1H), 2.58 (s, 1H), 2.33-2.14 (m,2H), 2.02-1.73 (m, 4H), 1.65 (s, 2H), 1.00 (s, 9H); MS (APCI+) m/z 587(M+H)⁺.

Example 166(2S,3R,4R,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedure described in Example138A-138B, and was isolated as the minor diastereomer. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.30 (dd, J=7.8, 1.7 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H),7.57 (d, J=1.7 Hz, 2H), 7.36 (td, J=7.5, 1.3 Hz, 1H), 7.20 (td, J=7.6,1.7 Hz, 1H), 5.24 (s, 1H), 4.98 (d, J=12.1 Hz, 1H), 4.67 (q, J=6.2 Hz,1H), 4.62 (d, J=12.2 Hz, 1H), 4.32 (d, J=10.8 Hz, 1H), 4.00 (d, J=3.5Hz, 1H), 3.86 (s, 3H), 3.48 (p, J=8.4 Hz, 1H), 2.37-2.26 (m, 2H), 2.20(dd, J=10.8, 3.5 Hz, 1H), 2.12-1.92 (m, 3H), 1.87 (t, J=7.9 Hz, 1H),1.11 (s, 2H), 1.06 (d, J=6.2 Hz, 1H), 1.03-0.91 (m, 12H); MS (APCI+) m/z603/605 (M+H)⁺ Br doublet.

Example 167(2S,3R,4S,5S)-3-tert-butyl-5-(2,6-difluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

The title compound was prepared using the procedure described in Example86, substituting Core 23 for Core 10. ¹H NMR (501 MHz, DMSO-d₆) δ ppm8.38 (d, J=2.4 Hz, 1H), 7.35 (s, 1H), 7.24 (p, J=7.6 Hz, 1H), 6.87 (t,J=8.7 Hz, 2H), 5.42 (d, J=7.6 Hz, 1H), 4.63 (s, 1H), 4.43 (d, J=13.6 Hz,1H), 4.39 (dd, J=7.7, 4.6 Hz, 1H), 4.14 (d, J=4.9 Hz, 1H), 3.93 (d,J=13.6 Hz, 1H), 3.82 (s, 3H), 2.61 (t, J=4.8 Hz, 1H), 1.07 (d, J=6.2 Hz,3H), 0.97 (s, 9H), 0.93-0.73 (m, 3H); MS (APCI+) m/z 575 (M+H)⁺.

Example 168(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 168A 1-allyl 2-ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 112C (104 g, 2.503 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (761.3 mg, 2.97 mmol)were dissolved in dimethylformamide (10 mL). The reaction was cooled to0° C., and potassium tert-butoxide (1M in tetrahydrofuran, 3.00 mL, 3.00mmol) was added dropwise. The reaction was stirred at ambienttemperature for 1 hour. The reaction was poured into saturated aqueousNH₄Cl (50 mL), extracted with methyl tert-butyl ether (3×50 mL), andpurified by silica gel chromatography (0% to 10% ethyl acetate indichloromethane) to provide the title compound (1.11 g, 75%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.96-7.91 (m, 1H), 7.78 (d, J=2.4 Hz,1H), 7.13-7.05 (m, 2H), 7.03-6.94 (m, 1H), 6.88 (d, J=2.4 Hz, 1H), 5.69(ddt, J=16.2, 10.4, 5.1 Hz, 1H), 5.63 (d, J=5.6 Hz, 1H), 5.07-4.93 (m,2H), 4.53 (d, J=2.0 Hz, 1H), 4.42 (dq, J=5.0, 1.7 Hz, 2H), 4.33 (dd,J=5.6, 1.0 Hz, 1H), 4.22 (d, J=13.2 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H),3.84 (dd, J=13.1, 0.9 Hz, 1H), 3.77 (s, 3H), 3.34 (p, J=8.8 Hz, 1H),2.57-2.52 (m, 1H), 2.31-2.19 (m, 2H), 2.05-1.81 (m, 5H), 1.17 (t, J=7.0Hz, 3H), 1.06 (s, 9H), 0.98-0.85 (m, 2H), 0.68-0.55 (m, 2H); MS (ESI+)m/z 591 (M+H)⁺.

Example 168B ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylate

Example 168A (1.09 g, 1.845 mmol) was dissolved in ethyl acetate (5 mL)and dichloromethane (5 mL) and treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (513.0 mg, 3.29 mmol) andtetrakis(triphenylphosphine)palladium (29.7 mg, 0.26 mmol). The reactionmixture was stirred at ambient temperature. After 1 hour, the reactionmixture was diluted with methyl tert-butyl ether (100 mL) and wasstirred with 15 mL of 10% aqueous Na₂CO₃ (100 mL) solution for 30minutes. The phases were then separated, and the organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography eluting with 5% to 10%ethyl acetate in dichloromethane to provide the title compound (706.3mg, 76%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.77 (d, J=2.4 Hz,1H), 7.62-7.56 (m, 1H), 7.18-7.11 (m, 2H), 7.03-6.97 (m, 1H), 6.89 (d,J=2.4 Hz, 1H), 4.59-4.50 (m, 1H), 4.20-4.02 (m, 5H), 3.71 (s, 3H), 3.60(t, J=6.7 Hz, 1H), 3.32-3.27 (m, 1H), 3.11 (dt, J=15.9, 6.4 Hz, 1H),2.31 (dd, J=6.7, 1.3 Hz, 1H), 2.23-2.09 (m, 2H), 2.02-1.73 (m, 4H), 1.19(t, J=7.1 Hz, 3H), 0.95 (s, 9H), 0.87 (dd, J=8.4, 1.8 Hz, 2H), 0.64-0.53(m, 2H); MS (ESI+) m/z 507 (M+H)⁺.

Example 168C 2-ethyl 1-isopropyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 168B (201.1 mg, 0.397 mmol) was dissolved in dichloromethane (3mL). Triethylamine (0.25 mL, 1.794 mmol) was added followed by isopropylchloroformate (1 M, 0.60 mL, 0.60 mmol). The reaction was stirred atambient temperature for 1 hour. The reaction was concentrated andpurified by silica gel chromatography (5%->10% ethyl acetate indichloromethane) to provide the title compound (235.5 mg, 100%). ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 7.97-7.88 (m, 1H), 7.78 (d, J=2.4 Hz,1H), 7.13-7.05 (m, 2H), 7.00 (dt, J=6.1, 3.3 Hz, 1H), 6.90 (d, J=2.3 Hz,1H), 5.59 (d, J=5.6 Hz, 1H), 4.66 (hept, J=6.2 Hz, 1H), 4.47 (d, J=1.9Hz, 1H), 4.30 (dd, J=5.6, 1.0 Hz, 1H), 4.21 (d, J=13.2 Hz, 1H), 4.14(qd, J=7.0, 1.8 Hz, 2H), 3.84 (d, J=13.2 Hz, 1H), 3.77 (s, 3H), 3.34 (p,J=8.8 Hz, 1H), 2.53-2.51 (m, 1H), 2.26 (dddq, J=11.8, 9.2, 5.7, 3.2 Hz,2H), 2.05-1.83 (m, 5H), 1.18 (t, J=7.0 Hz, 3H), 1.06 (s, 12H), 0.99-0.80(m, 5H), 0.62 (dd, J=6.6, 2.9 Hz, 2H); MS (ESI+) m/z 593 (M+H)⁺.

Example 168D(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

Example 168C (235.5 mg, 0.397 mmol) was dissolved in methanol (2 mL) andtetrahydrofuran (2 mL). Aqueous LiOH (1 M, 2 mL, 2 mmol) was added andthe reaction was heated to 50° C. for 16 hours. The reaction wasacidified with 2 M aqueous HCl to pH˜3 and stirred for 15 minutes. Thereaction was diluted with water (50 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to providethe title compound (222.3 mg, 99%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δppm 8.04-7.96 (m, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.09 (td, J=7.3, 6.5, 3.6Hz, 2H), 6.99 (dd, J=6.5, 2.6 Hz, 1H), 6.88 (d, J=2.3 Hz, 1H), 5.58 (d,J=5.8 Hz, 1H), 4.65 (hept, J=6.2 Hz, 1H), 4.42 (d, J=1.9 Hz, 1H), 4.28(d, J=5.7 Hz, 1H), 4.23 (d, J=13.4 Hz, 1H), 3.86 (d, J=13.4 Hz, 1H),3.77 (d, J=1.4 Hz, 3H), 3.33 (p, J=8.6 Hz, 1H), 2.55 (d, J=1.9 Hz, 1H),2.31-2.19 (m, 2H), 2.03-1.81 (m, 5H), 1.10-0.99 (m, 12H), 0.98-0.80 (m,5H), 0.62 (p, J=4.8 Hz, 2H); MS (ESI+) m/z 565 (M+H)⁺.

Example 169(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 169A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate

Example 133D (30 g, 69.0 mmol) and1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (21.56 g, 138 mmol) weredissolved in a mixture of dichloromethane and ethyl acetate (340 mLeach). Tetrakis(triphenylphosphine) palladium(0) (0.798 g, 0.690 mmol)was added, and the flask was sealed with a septum and the reaction wasstirred at ambient temperature for 15 minutes. The reaction was dilutedwith methyl tert-butyl ether (500 mL), 200 mL of 10% aqueous sodiumcarbonate was added, and the mixture was stirred for 10 minutes. Thelayers were separated, and the organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude material waspurified via flash chromatography, eluting with 0:100 to 60:40 ethylacetate:heptanes over 30 minutes on a 330 g silica gel column to provide19 g of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.06 (dd,J=5.0, 1.9 Hz, 1H), 7.73 (ddd, J=7.3, 1.8, 0.9 Hz, 1H), 6.87 (dd, J=7.3,5.0 Hz, 1H), 5.36 (p, J=6.1 Hz, 1H), 4.37 (t, J=4.8 Hz, 1H), 4.31-4.17(m, 3H), 3.69 (d, J=6.2 Hz, 1H), 2.62 (s, 1H), 2.19 (dd, J=6.3, 1.1 Hz,1H), 1.69 (br s, 1H), 1.39 (d, J=6.2 Hz, 3H), 1.36 (d, J=6.2 Hz, 3H),1.31 (t, J=7.1 Hz, 3H), 1.04 (s, 9H); MS (ESI+) m/z 351.2 (M+H)⁺.

Example 169B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate

To the solution of Example 169A (100 mg, 0.285 mmol) and triethylamine(0.119 mL, 0.856 mmol) in dichloromethane (3 mL) was addedcyclohexanecarbonyl chloride (0.057 mL, 0.428 mmol) in an ice-bath. Themixture was stirred in ice-bath for 30 minutes, and was allowed to warmto ambient temperature. Dichloromethane (10 mL) and saturated aqueousNH₄Cl (10 mL) were added and the organic layer was washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedvia chromatography, on a 4 g silica gel cartridge, eluting with ethylacetate in heptanes at 0-40% gradient to provide title compound 106 mg(81% yield). LC/MS (APCI+) m/z 461.45 (M+H)⁺.

Example 169C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-(cyclohexanecarbonyl)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate

To Example 169B (46 mg, 0.100 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (25.6 mg, 0.100 mmol) indimethylformamide (1 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (16.81 mg, 0.150 mmol, 0.75 mL, 1.0M intetrahydrofuran) was added dropwise. The mixture was stirred in ice-bathfor 30 minutes, and allowed to warm to ambient temperature.Dichloromethane and saturated aqueous NH₄Cl were added. The organiclayer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by chromatography, eluting withethyl acetate in heptane, on a 4 g silica gel cartridge using a 0-40%gradient to provide the title compound.

Example 169D(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-(cyclohexanecarbonyl)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylicacid

Example 169C was dissolved in methanol/6M aqueous LiOH (2 mL, 4:1) andthe mixture was stirred at 45° C. overnight. The mixture was adjusted pHto 1˜2 by adding 2M aqueous HCl and the resulting mixture was purifiedvia reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% Ato provide title compound 25 mg (41.2% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.20 (s, 1H), 7.98 (s, 1H), 7.77 (d, J=2.5 Hz, 1H), 6.84 (s, 2H),5.35 (s, 1H), 5.25 (m, 1H), 4.53 (d, J=2.9 Hz, 1H), 4.29 (d, J=13.1 Hz,1H), 4.25 (dd, J=6.2, 2.2 Hz, 1H), 3.98 (d, J=13.2 Hz, 1H), 3.76 (s,3H), 3.36-3.30 (m, 1H), 2.51 (s, 1H), 2.27-2.20 (m, 2H), 1.97-1.82 (m,4H), 1.59 (d, J=63.4 Hz, 5H), 1.31 (d, J=6.1 Hz, 3H), 1.28-1.17 (m, 6H),1.09 (s, 2H), 0.99 (s, 9H); MS (ESI+) m/z 608.2 (M+H)⁺.

Example 170(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 170A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-2-carboxylate

To a solution of Example 129C (430 mg, 1.104 mmol) and1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (345 mg, 2.208 mmol) inethyl acetate/dichloromethane (1:1, 4 mL) was addedtetrakis(triphenylphosphine)palladium(0) (22.78 mg, 0.022 mmol). Themixture was stirred at ambient temperature for 30 minutes, and LC/MSshowed the conversion was finished. Dichloromethane (10 mL) and aqueousNa₂CO₃ (2 M, 2 mL) were added and the mixture was stirred for 10minutes. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified via silica gelchromatography, eluting with ethyl acetate in heptanes at 0-50% gradientto provide title compound 300 mg, (89% yield). LC/MS (APCI+), m/z 306.3(M+H)⁺.

Example 170B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

To Example 170A (200 mg, 0.655 mmol) and triethylamine (0.274 mL, 1.965mmol) in dichloromethane (2 mL) cooling in an ice-bath was added(S)-tetrahydro-2H-pyran-2-carbonyl chloride (117 mg, 0.786 mmol). Themixture was stirred in an ice-bath for 20 minutes, and allowed to warmto room temperature. Dichloromethane (10 mL) and brine (10 mL) wereadded. The organic layer washed with water, dried over MgSO₄, filtered,and concentrated to provide title compound (270 mg, 99% yield) which wasused in the next step. LC/MS (APCI+) m/z 418.42 (M+H)⁺.

Example 170C(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylicacid

To Example 170B (50 mg, 0.120 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (36.8 mg, 0.144 mmol) indimethylformamide (1 mL) cooling in an ice-bath, potassium2-methylpropan-2-olate (20.16 mg, 0.180 mmol, 0.18 mL, 1.0M intetrahydrofuran) was added dropwise. The mixture was stirred in ice-bathfor 20 minutes, and was allowed to warm to ambient temperature. LC/MSshowed the conversion was finished. Dichloromethane and saturatedaqueous NH₄Cl (2 mL) were added. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified via chromatography, eluting with ethyl acetate in heptanes at a0-40% gradient to provide the ester of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylatewhich was dissolved in methanol (1.5 mL) and 6M aqueous LiOH (0.5 mL)and stirred at 450 for 17 hours. The mixture was adjusted pH to 1˜2 byadding 2M aqueous HCl and the reaction mixture was purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A toprovide the title compound 28 mg (41.4% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.07-8.01 (m, 1H), 7.76 (dd, J=2.4, 0.8 Hz, 1H), 7.10 (s,3H), 6.88 (dq, J=2.4, 0.9 Hz, 1H), 5.54 (s, 1H), 4.63 (s, 1H), 4.23 (d,J=5.9 Hz, 1H), 4.20-4.15 (dt, J=13.3, 0.9 Hz, 1H), 3.82 (dt, J=13.3, 0.9Hz, 1H), 3.77 (s, 1H), 3.75 (s, 3H), 3.34-3.30 (m, 2H), 2.64 (s, 1H),2.48 (s, 1H), 2.32 (s, 3H), 2.27-2.16 (m, 2H), 2.03-1.78 (m, 4H),1.71-1.24 (m, 6H), 1.00 (s, 9H); MS (ESI+) m/z 565.33 (M+H)⁺.

Example 171(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 171A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

Example 168B (172.5 mg, 0.340 mmol) was dissolved in dichloromethane (3mL). Triethylamine (0.25 mL, 1.794 mmol) was added followed by(S)-tetrahydro-2H-pyran-2-carbonyl chloride (70.0 mg, 0.471 mmol). Thereaction was stirred at ambient temperature for 1 hour. The reaction wasconcentrated and purified by silica gel chromatography (5%->10% ethylacetate in dichloromethane) to provide the title compound (188.1 mg,89%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.99 (dd, J=7.3, 1.9 Hz,1H), 7.75 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.3 Hz, 2H), 6.98 (dd, J=7.1,1.9 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 5.87 (s, 1H), 4.71 (s, 1H), 4.31(d, J=5.6 Hz, 1H), 4.19 (d, J=13.2 Hz, 1H), 4.08 (qd, J=7.1, 1.1 Hz,2H), 3.81 (dt, J=13.2, 0.9 Hz, 1H), 3.73 (s, 4H), 3.31 (p, J=9.1, 8.7Hz, 1H), 2.44 (d, J=1.8 Hz, 1H), 2.31-2.11 (m, 2H), 2.07-1.78 (m, 5H),1.73-1.21 (m, 8H), 1.13 (t, J=7.1 Hz, 3H), 1.02 (s, 9H), 0.99-0.83 (m,2H), 0.78-0.66 (m, 1H), 0.51 (dtd, J=9.0, 5.2, 3.0 Hz, 1H); MS (ESI+)m/z 593 (M+H)⁺.

Example 171B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 171A (161.9 mg, 0.262 mmol) was dissolved in methanol (1 mL),and tetrahydrofuran (1 mL). Aqueous LiOH (1 M, 1 mL, 1 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasacidified with 2 M aqueous HCl to pH˜3 and stirred for 15 minutes. Thereaction was diluted with water (25 mL) and extracted withdichloromethane (2×25 mL). The combined organic layers were washed withbrine (25 mL), dried over Na₂SO₄, filtered and concentrated to providethe title compound (138.9 mg, 90%)¹H NMR (400 MHz, DMSO-d₆, 120° C.) δppm 8.04-7.96 (m, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.09 (td, J=7.3, 6.5, 3.6Hz, 2H), 6.99 (dd, J=6.5, 2.6 Hz, 1H), 6.88 (d, J=2.3 Hz, 1H), 5.58 (d,J=5.8 Hz, 1H), 4.65 (hept, J=6.2 Hz, 1H), 4.42 (d, J=1.9 Hz, 1H), 4.28(d, J=5.7 Hz, 1H), 4.23 (d, J=13.4 Hz, 1H), 3.86 (d, J=13.4 Hz, 1H),3.77 (d, J=1.4 Hz, 3H), 3.49 (s, 2H), 3.33 (p, J=8.6 Hz, 1H), 2.55 (d,J=1.9 Hz, 1H), 2.31-2.19 (m, 2H), 2.03-1.81 (m, 5H), 1.10-0.99 (m, 12H),0.98-0.80 (m, 5H), 0.62 (p, J=4.8 Hz, 2H); MS (ESI+) m/z 565 (M+H)⁺.

Example 172(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 172A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-cyclopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 149B (0.135 g, 0.324 mmol), dried azeotropically with toluene,was dissolved in dimethylformamide (3.2 mL) and the mixture was cooledto 0° C. Potassium 2-methylpropan-2-olate (1M in tetrahydrofuran, 0.36mL, 0.360 mmol) was added dropwise, followed by dropwise addition of2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (0.100 g, 0.389 mmol).The reaction mixture was stirred at 0° C. for 45 minutes, and it waspoured into saturated aqueous NH₄Cl and extracted three times withmethyl tert-butyl ether. The combined organics were dried over Na₂SO₄,filtered and concentrated in vacuo. Silica gel chromatography, elutingwith 0 to 30% methyl tert-butyl ether-heptanes, provided the titlecompound, 0.051 g (27% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.94 (m,1H), 7.16-7.05 (m, 3H), 7.01-6.94 (m, 1H), 6.86 (d, J=2.6 Hz, 1H), 6.74(m, 1H), 5.74-5.59 (m, 2H), 5.05-4.95 (m, 2H), 4.54-4.47 (m, 1H), 4.40(dq, J=4.8, 1.4 Hz, 2H), 4.29 (dd, J=5.7, 1.1 Hz, 1H), 4.22-4.08 (m,3H), 3.88 (m, 1H), 3.63 (s, 3H), 2.52 (m, 1H), 1.99 (ddd, J=13.7, 8.5,5.4 Hz, 1H), 1.19-1.16 (m, 12H), 1.04 (s, 9H), 0.97-0.85 (m, 2H), 0.63(m, 2H); MS (ESI⁺) m/z 592.1 (M+H)⁺.

Example 172B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylate

Example 172A (0.051 g, 0.086 mmol) in ethyl acetate (0.5 mL) anddichloromethane (0.5 mL) was treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.027 g, 0.172 mmol) andtetrakis(triphenylphosphine)palladium(0) (1 mg, 0.865 μmol), and thereaction was stirred at room temperature. After 1 hour, the reactionmixture was diluted with 3 mL methyl tert-butyl ether and was stirredwith 3 mL of 10% aqueous Na₂CO₃ solution for 30 minutes. The phases wereseparated, and the organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to provide the crude titlecompound (38 mg, 87% yield), which was used in the following reactionwithout further purification. MS (APCI⁺) m/z 508.6 (M+H)⁺.

Example 172C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-cyclopropylphenyl)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

A stock solution of (S)-tetrahydrofuran-2-carbonyl chloride was preparedas follows: 101 mg (0.87 mmol) of (S)-tetrahydrofuran-2-carboxylic acidwas refluxed in 0.9 mL of thionyl chloride for 1 hour, and the solutionwas cooled to room temperature and concentrated in vacuo, with excessthionyl chloride chased by dichloromethane (3×1 mL). The resulting crudeacid chloride was dissolved in 2.2 mL dichloromethane and was used inthe present reaction and that of Example 173D. Stock solution (0.4 mL,0.150 mmol) of crude (S)-tetrahydrofuran-2-carbonyl chloride was addedto a solution of Example 172B (0.038 g, 0.075 mmol) in 1 mLdichloromethane. Pyridine (0.073 mL, 0.898 mmol) was added, and thereaction was stirred at room temperature for 1 hour. After this time,the mixture was diluted with ethyl acetate and washed three times withwater and once with brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo, and the crude title compound thusobtained was taken directly into the next reaction without furtherpurification. MS (APCI⁺) m/z 606.6 (M+H)⁺.

Example 172D(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 172C (0.045 g, 0.075 mmol) and lithium hydroxide (1M aqueous,0.75 mL, 0.75 mmol) were stirred in tetrahydrofuran (0.75 mL) andmethanol (0.75 mL) overnight at 45° C., and at 50° C. for 1 hour. Thereaction mixture was cooled to room temperature and acidified to pH˜2with 1N aqueous HCl, and the mixture was extracted with dichloromethane(3×3 mL). The combined organic extracts were dried over Na₂SO₄, filteredand concentrated in vacuo, and the crude product was purified by silicagel chromatography, eluting with 0 to 100% ethyl acetate-heptanes toprovide the title compound, 0.006 g (14% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.07 (m, 1H), 7.08 (m, 3H), 6.96 (m, 1H), 6.81 (m, 1H),6.71 (d, J=8.5 Hz, 1H), 5.84 (m, 1H), 4.61 (m, 1H), 4.27 (m, 1H), 4.18(d, J=12.6 Hz, 1H), 3.83 (d, J=12.6 Hz, 1H), 3.70 (m, 1H), 3.60 (s, 3H),3.57 (m, 2H), 2.56 (m, 1H), 2.04-1.83 (m, 3H), 1.62 (m, 2H), 1.15 (s,9H), 0.99 (s, 9H), 0.90 (m, 2H), 0.68-0.51 (m, 2H); MS (ESI⁺) m/z 578.2(M+H)⁺.

Example 173(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 173A 5-bromo-3-(bromomethyl)-2-methoxypyridine

To a solution of 5-bromo-2-methoxy-3-methylpyridine (Ark; 2.981 g, 14.75mmol) in CCl₄ (12 mL) was added N-bromosuccinimide (2.89 g, 16.23 mmol)and (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.036 g,0.221 mmol). The reaction mixture was stirred at 80° C. for 2 hours, andit was cooled in an ice bath and filtered through diatomaceous earth.The solution was concentrated in vacuo to provide the title compound(2.0538 g, 50% yield). ¹H NMR (501 MHz, CDCl₃) δ ppm 8.17 (d, J=2.4 Hz,1H), 7.74 (d, J=2.4, 1H), 4.43 (s, 2H), 4.01 (s, 3H).

Example 173B (2S,3R,4S,5S)-1-allyl 2-ethyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-5-(2-cyclopropylphenyl)pyrrolidine-1,2-dicarboxylate

Example 149B (0.370 g, 0.890 mmol), dried azeotropically with toluene,was dissolved in dimethyl formamide (3.2 mL) and cooled to 0° C.Potassium 2-methylpropan-2-olate (1M in tetrahydrofuran, 0.98 mL, 0.980mmol) was added dropwise, followed by Example 173A (0.300 g, 1.068mmol). The reaction mixture was stirred at 0° C. for 45 minutes, and themixture was poured into saturated aqueous NH₄Cl and extracted threetimes with methyl tert-butyl ether. The combined organics were driedover Na₂SO₄, filtered, and concentrated in vacuo. Silica gelchromatography, eluting with 0 to 40% methyl tert-butyl ether-heptanes,provided the impure title compound, 0.246 g (45% yield). ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.02 (m, 1H), 7.94-7.87 (m, 1H), 7.14-7.06 (m, 2H),7.05-6.97 (m, 1H), 6.94 (m, 1H), 5.75-5.61 (m, 2H), 5.02 (m, 2H), 4.53(m, 1H), 4.43 (m, 2H), 4.33 (m, 1H), 4.24-4.14 (m, 3H), 3.96-3.89 (m,1H), 3.79 (s, 3H), 2.52 (m, 1H), 2.04-1.94 (m, 1H), 1.21 (t, J=6.6 Hz,3H), 1.07 (s, 9H), 0.90 (m, 2H), 0.67-0.54 (m, 2H); MS (ESI⁺) m/z 615.0(M+H)⁺.

Example 173C (2S,3R,4S,5S)-ethyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylate

The impure product from Example 173B (0.246 g, 0.400 mmol) in ethylacetate (2 mL) and dichloromethane (2 mL) was treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.125 g, 0.799 mmol) andtetrakis(triphenylphosphine)palladium(0) (4.6 mg, 4.00 μmol), and thereaction mixture was stirred at room temperature. After 1 hour, thereaction mixture was diluted with 15 mL methyl tert-butyl ether and themixture was stirred with 15 mL of 10% aqueous Na₂CO₃ solution for 30minutes. The mixture was transferred to a separatory funnel, the phaseswere separated, and the organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to provide the crude titlecompound, which was taken directly into the following reaction withoutfurther purification. MS (APCI⁺) m/z 533.5 (M+H)⁺.

Example 173D (2S,3R,4S,5S)-ethyl4-((5-bromo-2-methoxypyridin-3-yl)methoxy)-3-(tert-butyl)-5-(2-cyclopropylphenyl)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate

Stock (S)-tetrahydrofuran-2-carbonyl chloride solution from Example 172C(1.8 mL, 0.723 mmol) was added to a solution of Example 173C (0.192 g,0.361 mmol) in 1 mL dichloromethane. Pyridine (0.35 mL, 4.34 mmol) wasadded, and the reaction mixture was stirred at room temperature for 1hour. The reaction mixture was diluted with ethyl acetate and washedthree times with water and once with brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo to provide the crudetitle compound, which was taken directly into the next reaction withoutfurther purification. MS (APCI⁺) m/z 631.5 (M+H)⁺.

Example 173E(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 173D (0.227 g, 0.361 mmol) and lithium hydroxide (1M aqueous, 3mL, 3 mmol) were stirred in tetrahydrofuran (3 mL) and methanol (3 mL)at 45° C. overnight. The reaction mixture was cooled to room temperatureand acidified to pH˜2 with 1N aqueous HCl, and the mixture was extractedwith dichloromethane (3×10 mL). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product wassubjected to silica gel chromatography, eluting with 0 to 5%methanol-ethyl acetate. The material thus obtained was further purifiedby reverse-phase HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column(30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A,1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 minlinear gradient 95-5% A) to provide the title compound, 0.048 g (22%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.98 (m, 2H), 7.16-7.05 (m, 2H),6.98 (dd, J=7.0, 2.0 Hz, 1H), 6.87 (dd, J=2.4, 1.2 Hz, 1H), 5.90 (m,1H), 4.71 (d, J=1.8 Hz, 1H), 4.32 (d, J=5.7 Hz, 1H), 4.23 (m, 1H), 4.07(m, 1H), 3.84 (m, 1H), 3.77 (s, 3H), 3.70 (m, 1H), 3.61 (m, 1H), 2.53(m, 1H), 2.05-1.88 (m, 3H), 1.87-1.72 (m, 1H), 1.63 (m, 1H), 1.03 (s,9H), 0.98-0.81 (m, 2H), 0.65 (m, 1H), 0.60-0.49 (m, 1H); MS (ESI⁺) m/z601.1 (M+H)⁺.

Example 174(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 174A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

To a solution Example 170 (80 mg, 0.192 mmol) and2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene (61.9 mg, 0.230mmol) in dimethylformamide (5 mL) cooled in an ice bath was addedpotassium 2-methylpropan-2-olate (32.2 mg, 0.287 mmol) dropwise. Thereaction was stirred in an ice-bath for 20 minutes, and stirred at roomtemperature for 30 minutes. Dichloromethane and saturated aqueousammonium chloride solution were added. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified via chromatography, eluting with ethyl acetate in heptane,using a 0-30% gradient to provide the title compound. LC/MS (APCI+) m/z606 (M+H)⁺.

Example 174B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 174A was dissolved in methanol (2 mL) and aqueous LiOH solution(6N, 0.5 mL). The mixture was stirred at 45° C. overnight, adjusted pHto 1˜2 by adding 2M aqueous HCl. The reaction mixture was purified byreverse-phase HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30mm×75 mm), with a gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A,1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 minlinear gradient 95-5% A) to provide the title compound (48 mg, 0.083mmol, 43.4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.08-7.99 (m, 1H),7.43 (dd, J=8.7, 2.4 Hz, 1H), 7.07 (s, 3H), 7.03-6.93 (m, 2H), 5.54 (s,1H), 4.62 (d, J=1.9 Hz, 2H), 4.30-4.20 (m, 2H), 3.78 (s, 2H), 3.74 (s,3H), 2.31 (s, 3H), 1.68-1.28 (m, 6H), 1.00 (s, 9H); MS (ESI+) m/z 578(M+H)⁺.

Example 175(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 175A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

To a solution Example 170B (80 mg, 0.192 mmol) and1-(bromomethyl)-2-methoxy-4-(trifluoromethyl)benzene (56.7 mg, 0.217mmol) in dimethylformamide (5 mL) cooled in an ice bath was addedpotassium 2-methylpropan-2-olate (32.2 mg, 0.287 mmol) dropwise. Thereaction was stirred in an ice-bath for 20 minutes, and stirred at roomtemperature for 30 minutes. Dichloromethane and saturated aqueousammonium chloride solution were added. The organic layer washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified through chromatography, eluting with ethyl acetate in heptane,using a 0-30% gradient to provide the title compound. LC/MS (APCI+) m/z606 (M+H)⁺.

Example 175B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 175A was dissolved in methanol (2 mL) and aqueous LiOH solution(6N, 0.5 mL). The mixture was stirred at 45° C. overnight, and adjustedpH to 1˜2 by adding 2M aqueous HCl. The reaction mixture was purified byreverse-phase HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30mm×75 mm), with a gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A,1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 minlinear gradient 95-5% A) to provide the title compound (40 mg, 36.1%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.07-7.96 (m, 1H), 7.17 (d,J=7.9 Hz, 1H), 7.10 (s, 2H), 7.05 (d, J=1.6 Hz, 1H), 7.01-6.94 (m, 1H),6.79 (d, J=7.9 Hz, 1H), 5.52 (s, 1H), 4.63 (s, 2H), 4.27-4.22 (m, 1H),4.20 (d, J=5.8 Hz, 1H), 3.88 (d, J=13.8 Hz, 1H), 3.79 (s, 2H), 3.73 (s,3H), 2.45 (s, 1H), 2.31 (s, 3H), 1.71-1.27 (m, 6H), 1.00 (s, 9H); MS(ESI+) m/z 578.1 (M+H)⁺.

Example 176(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 176A(2S,3R,4S,5S)-1-((allyloxy)carbonyl)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropylphenyl)pyrrolidine-2-carboxylicacid

Example 130F (0.217 g, 0.520 mmol), dried azeotropically with toluene,was dissolved in dimethyl formamide (5.2 mL) and the mixture was cooledto 0° C. Potassium 2-methylpropan-2-olate (1M in tetrahydrofuran, 0.64mL, 0.640 mmol) was added dropwise, followed by dropwise addition ofExample 130C (0.177 g, 0.691 mmol). The reaction mixture was stirred at0° C. for 45 minutes, poured into saturated aqueous NH₄Cl and extractedthree times with methyl tert-butyl ether. The combined organics weredried over Na₂SO₄, filtered, and concentrated in vacuo. Silica gelchromatography, eluting with 0 to 30% methyl tert-butyl ether-heptanesand flushing the column with 3:1:4 ethyl acetate-ethanol-heptanes,provided the impure title compound as a colorless residue, 0.059 g (20%yield). The compound was used in the next step without furtherpurification. MS (APCI⁺) m/z 565.6 (M+H)⁺.

Example 176B(2S,3R,4S,5S)-3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropylphenyl)pyrrolidine-2-carboxylicacid

Example 176A (0.063 g, 0.112 mmol) was dissolved in ethyl acetate (0.6mL) and dichloromethane (0.6 mL) and treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.035 g, 0.223 mmol) andtetrakis(triphenylphosphine)palladium (1.3 mg, 1.116 μmol). The reactionwas stirred at room temperature for 30 minutes, diluted with 5 mL methyltert-butyl ether, and stirred with 4 mL of 10% aqueous Na₂CO₃ solutionfor 15 minutes. The phases were separated, and the organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude title compound thus obtained was taken directly intothe next reaction without further purification. MS (APCI⁺) m/z 481.5(M+H)⁺.

Example 176C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

A solution of (S)-tetrahydro-2H-pyran-2-carbonyl chloride (200 mg/mL indichloromethane, prepared from (S)-tetrahydro-2H-pyran carboxylic acidand oxalyl chloride; 0.16 mL of solution used, 0.032 g, 0.212 mmol) wasadded to a solution of Example 176B (0.051 g, 0.106 mmol) and pyridine(0.103 mL, 1.272 mmol) in dichloromethane (1.5 mL). The reaction mixturewas stirred at room temperature. After 1 hour, the mixture was dilutedwith dichloromethane (5 mL), washed three times with water (1 mL each),and once with brine (1 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified byreverse-phase HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acidin water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A,1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 minlinear gradient 95-5% A to provide the title compound, 0.012 g (19%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.06 (dd, J=7.8, 1.4 Hz, 1H),7.73 (m, 1H), 7.22 (m, 2H), 7.07 (t, J=7.5 Hz, 1H), 6.82 (d, J=2.3 Hz,1H), 5.60 (m, 1H), 4.69 (d, J=1.7 Hz, 1H), 4.28-4.16 (m, 2H), 3.77 (m,2H), 3.74 (s, 3H), 3.56 (m, 1H), 3.34-3.17 (m, 2H), 3.06 (m, 2H), 2.50(m, 1H), 2.22 (m, 2H), 2.02-1.78 (m, 4H), 1.66 (m, 1H), 1.54 (m, 1H),1.42-1.27 (m, 6H), 1.13 (d, J=6.8 Hz, 3H), 1.02 (s, 9H); MS (ESI⁺) m/z593.5 (M+H)⁺.

Example 177(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 144E-Example 144F, substituting(S)-tetrahydro-2H-pyran-2-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid in Example 144E. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 8.05-7.97 (m, 1H), 7.66 (dd, J=8.5, 1.4 Hz, 1H),7.58-7.49 (m, 2H), 7.34 (ddd, J=8.0, 7.0, 1.2 Hz, 1H), 7.22 (s, 1H),7.12 (td, J=6.9, 6.1, 4.0 Hz, 2H), 6.98 (dd, J=6.4, 2.5 Hz, 1H), 5.59(d, J=5.7 Hz, 1H), 4.64 (hept, J=6.3 Hz, 1H), 4.44 (d, J=1.9 Hz, 1H),4.39-4.30 (m, 2H), 3.98 (dd, J=14.1, 1.4 Hz, 1H), 3.91 (s, 3H),2.61-2.55 (m, 1H), 1.96 (tt, J=8.5, 5.4 Hz, 1H), 1.08-0.99 (m, 12H),0.95-0.77 (m, 5H), 0.58 (dtt, J=9.3, 7.1, 4.6 Hz, 2H); MS (ESI+) m/z 565(M+H)⁺.

Example 178(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 178A 1-allyl 2-ethyl(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 144C (6.92 g, 15.23 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (5.16 g, 19.11mmol) were dissolved in dimethylformamide (61 mL). The reaction wascooled to 0° C., and potassium tert-butoxide (1M in tetrahydrofuran,19.0 mL, 19.0 mmol) was added dropwise. The reaction was stirred atambient temperature for 1 hour. The reaction was poured into saturatedaqueous NH₄Cl (50 mL), diluted with water (100 mL) and extracted withmethyl tert-butyl ether (3×100 mL). The combined organics were washedwith water (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography (0%to 5% ethyl acetate in dichloromethane) to provide the title compound(9.80 mg, 52%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.34-8.25 (m,1H), 7.96 (dd, J=7.8, 1.8 Hz, 1H), 7.45 (dd, J=8.0, 1.3 Hz, 1H), 7.22(td, J=7.6, 1.3 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.08 (td, J=7.6, 1.8Hz, 1H), 5.72 (ddt, J=17.5, 10.0, 5.0 Hz, 1H), 5.33 (d, J=5.6 Hz, 1H),5.09-4.99 (m, 2H), 4.54 (d, J=2.0 Hz, 1H), 4.47-4.37 (m, 4H), 4.34 (dd,J=13.6, 0.9 Hz, 1H), 4.12 (qd, J=7.1, 1.2 Hz, 2H), 3.88 (s, 3H), 2.52(t, J=1.5 Hz, 1H), 1.15 (t, J=7.1 Hz, 3H), 1.05 (s, 9H); MS (ESI+) m/z643 & 645 (M+H)⁺.

Example 178B ethyl(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 178A (4.925 mg, 7.65 mmol) was dissolved in ethyl acetate (15mL) and dichloromethane (15 mL) and treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (2.39 g, 15.31 mmol) andtetrakis(triphenylphosphine)palladium (94.5 mg, 0.082 mmol). Thereaction mixture was stirred at ambient temperature. After 1 hour, thereaction mixture was diluted with methyl tert-butyl ether (100 mL) andstirred with 10% aqueous Na₂CO₃ (100 mL) solution for 30 minutes. Thephases were then separated, and the organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated to provide the titlecompound (4.28 g, 100%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.35(dd, J=2.5, 1.2 Hz, 1H), 7.75 (dd, J=7.8, 1.8 Hz, 1H), 7.48 (dd, J=7.9,1.2 Hz, 1H), 7.26 (td, J=7.5, 1.3 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.12(td, J=7.6, 1.8 Hz, 1H), 5.61-5.43 (m, 1H), 5.07-4.92 (m, 1H), 4.35 (t,J=5.5 Hz, 1H), 4.28 (d, J=14.1 Hz, 1H), 4.18-4.04 (m, 2H), 3.89-3.78 (m,4H), 3.65 (t, J=6.2 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.95 (s, 9H); MS(ESI+) m/z 559 & 561 (M+H)⁺.

Example 178C ethyl(2S,3R,4S,5S)-5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(S)-Tetrahydro-2H-pyran-2-carboxylic acid (1.21 g, 9.30 mmol) wasdissolved in dichloromethane (40 mL). Oxalyl chloride (2M indichloromethane, 4.65 mL, 9.30 mmol) was added followed bydimethylformamide (50 μL). The reaction was stirred at ambienttemperature for 3 hours. The reaction was chilled to 0° C. and Example178B (4.28 g, 7.65 mmol) and triethylamine (4 mL, 28.7 mmol) dissolvedin dichloromethane (20 mL) were added. The reaction was allowed to warmto ambient temperature and was stirred at ambient temperature for 17hours. The mixture was diluted with dichloromethane (100 mL) and washedtwice with saturated aqueous NaHCO₃ and once with brine. The organiclayer was dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography, eluting with 5% ethyl acetate indichloromethane to provide the title compound (3.33 g, 65%). ¹H NMR (400MHz, DMSO-d₆, 120° C.) δ ppm 8.29 (d, J=1.7 Hz, 1H), 8.05 (d, J=7.9 Hz,1H), 7.49 (d, J=7.9 Hz, 1H), 7.24 (s, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.11(s, 1H), 5.77 (s, 1H), 4.73 (s, 1H), 4.38 (d, J=6.0 Hz, 1H), 4.32 (d,J=13.7 Hz, 1H), 4.09 (qd, J=7.1, 2.2 Hz, 2H), 3.98-3.90 (m, 1H), 3.87(s, 3H), 3.83-3.73 (m, 1H), 3.51-3.20 (m, 2H), 2.45-2.38 (m, 1H), 1.68(s, 1H), 1.45 (d, J=54.8 Hz, 5H), 1.14 (t, J=7.1 Hz, 3H), 1.02 (s, 9H);MS (ESI+) m/z 671 & 673 (M+H)⁺.

Example 178D(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 178C (66.9 mg, 0.100 mmol) was dissolved in methanol (1 mL), andtetrahydrofuran (1 mL). Aqueous LiOH (1 M, 1.0 mL, 01.0 mmol) was addedand the reaction was heated to 50° C. for 16 hours. The reaction wasacidified with 1 M aqueous HCl to pH˜2, then diluted to 25 mL withwater. The aqueous layer was extracted with dichloromethane (2×25 mL).The combined organic layers were washed with brine (25 mL), dried overNa₂SO₄, filtered and concentrated to provide the title compound (62.4mg, 97%). ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.32-8.24 (m, 1H),8.13 (d, J=7.9 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.23 (s, 1H), 7.15 (d,J=2.4 Hz, 1H), 7.10 (s, 1H), 5.74 (s, 1H), 4.69 (s, 1H), 4.42-4.28 (m,2H), 3.97 (dd, J=13.8, 0.9 Hz, 1H), 3.87 (d, J=0.9 Hz, 3H), 3.80 (d,J=11.5 Hz, 1H), 2.48 (s, 1H), 1.67 (d, J=12.3 Hz, 1H), 1.61-1.19 (m,5H), 1.02 (d, J=1.0 Hz, 9H); MS (ESI+) m/z 643 & 645 (M+H)⁺.

Example 179(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 179A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

To Core 24 (1.43 g, 4.10 mmol) in toluene (4.77 mL) and saturatedaqueous NaHCO₃ (4.77 mL) was added allyl carbonochloridate (0.463 mL,4.23 mmol) dropwise at ambient temperature. The mixture was stirred atambient temperature for 16 hours. Ethyl acetate (30 mL) and water (25mL) were added and the organic layer was washed with brine andconcentrated. The resulting material was purified on a 24 g silica gelcartridge eluting with a gradient of 0-65% ethyl acetate/heptanes over aperiod of 20 minutes to provide (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate(1.64 g, 3.79 mmol, 92% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.83 (d,J=7.7 Hz, 1H), 7.19-7.13 (m, 1H), 7.13-7.05 (m, 2H), 5.72 (bs, 1H), 5.66(dd, J=8.8, 2.9 Hz, 1H), 5.58 (d, J=8.8 Hz, 1H), 4.97 (d, 2H), 4.53 (d,J=3.8 Hz, 1H), 4.42 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 3.03 (d, J=3.5 Hz,1H), 2.84 (dq, J=14.8, 7.4 Hz, 1H), 2.58 (dq, J=15.1, 7.6 Hz, 1H), 1.26(t, J=7.1 Hz, 3H), 1.18 (t, J=7.5 Hz, 3H), 1.00 (s, 9H); MS (APCI+) m/z433 (M+H)⁺.

Example 179B (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

To potassium dichromate (6.02 g, 20.48 mmol) in 6N aqueous HCl (93 mL)was added zinc (6.84 g, 105 mmol) portionwise under N₂ atmosphere atroom temperature. After the almost complete dissolution of zinc (˜2hours) provided a clear light blue solution, the formed chromium(II)chloride was transferred via cannula to the refluxing solution ofExample 179A (1.64 g, 3.79 mmol) in ethanol (79 mL) under N₂. Thereaction mixture was refluxed at 86° C. internally for 20 hours, cooled,and concentrated. The mixture was extracted with dichloromethane threetimes. The organic phase was washed with saturated aqueous NaHCO₃solution and brine, dried over MgSO₄, filtered, and concentrated. Theresidue (1.65 g) was subjected to re-esterification. Acetyl chloride (2mL, 28.13 mmol) was added slowly to an ice-cooled flask containingethanol (6 mL). After the addition was complete, the reaction wasstirred at room temperature for 5 minutes before pouring the resultingHCl/ethanol solution into a separate flask containing the crudeester/acid mixture. The mixture was heated to 65° C. for an additionalhour, at which point nearly complete conversion was noted. The mixturewas cooled to room temperature and concentrated. The crude material waspurified on a 24 g cartridge eluting with a gradient of 0-70% ethylacetate/heptanes over a period of 20 minutes to provide(2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate(0.802 g, 1.998 mmol, 52.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.77(d, J=7.6 Hz, 1H), 7.25-7.05 (m, 3H), 5.69 (d, J=101.2 Hz, 1H), 5.26 (s,1H), 4.90 (d, 1H), 4.73-4.29 (m, 4H), 4.20 (qd, J=7.1, 1.6 Hz, 2H), 2.73(tt, J=14.5, 7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.16 (t, J=7.5 Hz,3H), 1.03 (s, 9H); MS (APCI+) m/z 402 (M+H)⁺.

Example 179C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

Example 179B (0.8 g, 1.993 mmol) was dissolved in ethanol (9.96 mL) andsodium borohydride (0.151 g, 3.99 mmol) was added after cooling thereaction to <−10° C. in an ice/acetone bath. The ice bath was removedand the mixture was allowed to warm to room temperature over 20 minutes.The reaction mixture was concentrated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organics wereconcentrated and purified using a 40 g silica gel cartridge and elutingwith 0-2% methanol/dichloromethane over a period of 20 minutes toprovide (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate,2173 (601 mg, 1.489 mmol, 74.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.92 (s, 1H), 7.13-7.02 (m, 3H), 5.67 (d, J=107.5 Hz, 1H), 5.23 (m, 1H),5.07 (d, J=6.6 Hz, 1H), 4.85 (m, 1H), 4.61 (s, 1H), 4.47-4.27 (m, 3H),4.24 (d, J=4.9 Hz, 1H), 4.14 (qd, J=7.1, 1.9 Hz, 2H), 2.69 (dq, J=14.4,7.2 Hz, 1H), 2.54 (dd, J=14.7, 7.5 Hz, 1H), 2.23 (s, 1H), 1.22 (t, J=7.1Hz, 3H), 1.16 (t, J=7.4 Hz, 3H), 0.95 (s, 9H); MS (APCI+) m/z 404(M+H)⁺.

Example 179D (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

Example 179C (400 mg, 0.991 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (428 mg, 1.586mmol) were dissolved in dry dimethylformamide (5 mL). After cooling inan ice bath, potassium 2-methylpropan-2-olate (1.437 mL, 1.437 mmol)solution was added dropwise over 4 minutes. After 60 minutes, thereaction was acidified with 1M aqueous HCl (1.2 mL) and warmed to roomtemperature. The reaction mixture was diluted with water (20 mL) andextracted with dichloromethane. The organic extracts were loaded onto a24 g silica gel column and eluted with a gradient of 0-80% ethylacetate/heptanes over 20 minutes to provide (2S,3R,4S,5S)-1-allyl2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate(421 mg, 0.710 mmol, 71.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.33(dd, J=2.5, 1.2 Hz, 1H), 7.91 (s, 1H), 7.15-6.93 (m, 4H), 5.66 (d,J=128.9 Hz, 1H), 5.18 (d, J=5.4 Hz, 3H), 5.00-4.53 (m, 1H), 4.47 (d,J=1.8 Hz, 2H), 4.31 (s, 2H), 4.28 (d, J=14.6 Hz, 2H), 4.06 (qt, J=7.1,3.6 Hz, 2H), 3.82 (d, J=14.6 Hz, 4H), 2.73 (dq, J=14.9, 7.4 Hz, 1H),2.54 (dt, J=14.7, 7.5 Hz, 1H), 1.14 (t, J=7.6 Hz, 3H), 1.08 (t, J=7.1Hz, 3H), 1.00 (s, 9H); MS (APCI+) m/z 593 (M+H)⁺.

Example 179E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

To a solution of Example 179D (420 mg, 0.709 mmol) in acetonitrile/water(1.24 mL, 10:1) was added tetrakis(triphenylphosphine)palladium(0)(18.02 mg, 0.016 mmol) and diethylamine (0.147 mL, 1.417 mmol) Themixture was stirred at room temperature overnight. Dichloromethane andwater were added, and the organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated. The crude material was purifiedby chromatography, eluting on 12 g silica gel cartridge with a gradientof 0-70% ethyl acetate/heptanes over 20 minutes to provide(2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(321 mg, 0.631 mmol, 89% yield). ¹H NMR (501 MHz, DMSO-d₆) δ ppm8.41-8.30 (s, 1H), 7.67-7.55 (d, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.19-7.09(m, 2H), 7.05 (ddd, J=8.5, 5.7, 3.0 Hz, 1H), 4.25 (d, J=4.5 Hz, 1H),4.22 (d, J=13.8 Hz, 2H), 4.17-4.07 (m, 2H), 3.96 (dd, J=4.5, 1.6 Hz,1H), 3.83 (s, 3H), 3.72 (d, J=13.9 Hz, 1H), 3.59 (t, J=7.1 Hz, 1H), 3.12(t, J=7.8 Hz, 1H), 2.68 (dq, J=15.0, 7.5 Hz, 1H), 2.59 (dq, J=14.9, 7.5Hz, 1H), 2.34 (dd, J=6.8, 1.5 Hz, 1H), 1.22-1.17 (t, 3H), 1.17-1.13 (t,3H), 0.95 (s, 9H); MS (APCI+) m/z 509 (M+H)⁺.

Example 179F (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of Example 179E (320 mg, 0.629 mmol) in dichloromethane(2.5 mL) at 0° C. was added triethylamine (0.395 mL, 2.83 mmol) followedby tetrahydro-2H-pyran-2-carbonyl chloride (159 mg, 1.070 mmol) as asolution in 2 mL dichloromethane. After stirring for 15 minutes, thereaction was quenched with 5 mL of saturated aqueous sodium bicarbonate.The crude material was chromatographed three times using a 24 g silicagel cartridge (3 times with a gradient of 0-80% ethyl acetate/heptanesover a period of 20 minutes to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(166 mg, 0.267 mmol, 42.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27(d, J=2.4 Hz, 1H), 8.02-7.94 (d, 1H), 7.20 (s, 1H), 7.13 (s, 2H), 7.04(d, J=7.5 Hz, 1H), 5.56 (s, 1H), 4.69 (s, 1H), 4.32-4.20 (m, 2H), 4.09(qd, J=7.0, 3.0 Hz, 2H), 3.85 (s, 3H), 3.80 (d, J=13.8 Hz, 1H), 3.72 (d,J=11.4 Hz, 1H), 3.41 (bs, 2H), 2.75 (dt, J=15.1, 7.6 Hz, 1H), 2.66 (dd,J=14.9, 7.4 Hz, 1H), 2.42 (d, J=1.8 Hz, 1H), 1.65 (d, J=12.9 Hz, 1H),1.52 (d, J=11.9 Hz, 2H), 1.34 (s, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.14 (t,J=7.1 Hz, 3H), 1.03 (s, 9H); MS (APCI+) m/z 621 (M+H)⁺. Also obtainedwas (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((R)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(168 mg, 0.271 mmol, 43.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27(s, 1H), 7.78 (s, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.09-7.03 (m, 2H), 6.97(d, J=8.3 Hz, 1H), 5.31 (d, J=5.6 Hz, 1H), 4.94 (s, 1H), 4.29-4.20 (m,2H), 4.13 (qd, J=7.1, 2.2 Hz, 2H), 3.91 (bs, 2H), 3.85 (s, 3H),3.83-3.76 (m, 1H), 3.26 (bs, 1H), 2.75 (dq, J=14.9, 7.6 Hz, 1H), 2.63(dt, J=14.8, 7.5 Hz, 1H), 2.57 (d, J=2.4 Hz, 1H), 1.77 (s, 1H), 1.51 (s,2H), 1.41 (s, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.03(s, 9H); MS (APCI+) m/z 621 (M+H)⁺.

Example 179G(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of the first eluting diastereomer from Example 179F (156mg, 0.251 mmol) in tetrahydrofuran (0.760 mL), methanol (0.760 mL), andwater (0.760 mL) was added lithium hydroxide, H₂O (73.8 mg, 1.759 mmol).The reaction mixture was heated at 45° C. for 16 hours. LC/MS showeddesired product and the solvent was removed under a stream of nitrogen.Water (0.5 mL) was added to the crude material. The mixture wasacidified with 1M aqueous HCl (1.53 mL) to pH˜6, extracted once withheptanes (discarded), and once with dichloromethane. The solvent wasevaporated in vacuo. The resulted crude material was chromatographedusing a 4 g silica gel cartridge with a gradient of 0-10%methanol/dichloromethane over a period of 10 minutes to provide(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid (87 mg, 0.147 mmol, 58.4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.26 (s, 1H), 8.05 (d, J=7.3 Hz, 1H), 7.16 (s, 1H), 7.10 (s, 2H), 7.03(m, 1H), 5.56 (s, 1H), 4.65 (s, 1H), 4.28 (d, J=14.0 Hz, 1H), 4.23 (d,J=5.8 Hz, 1H), 3.86 (d, 4H), 3.73 (d, J=11.5 Hz, 1H), 3.42 (bs, 2H),2.79-2.69 (m, 1H), 2.64 (dq, J=15.0, 7.6 Hz, 1H), 2.48 (m, 1H),1.71-1.60 (m, 1H), 1.52 (m, 2H), 1.34 (m, 3H), 1.21 (t, J=7.5 Hz, 3H),1.02 (s, 9H); MS (APCI+) m/z 593 (M+H)⁺.

Example 180(2S,3R,4S,5S)-5-([1,1′-biphenyl]-2-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 178C (98.5 mg, 0.147 mmol), phenylboronic acid (30.5 mg, 0.250mmol) and cesium fluoride (75.2 mg, 0.495 mmol) were dissolved indioxane (1 mL). The reaction was purged with nitrogen for 5 minutes, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (9.0 mg, 0.011 mmol) was added. The reaction waspurged with nitrogen and heated to 100° C. for 1 hour. Methanol (1 mL)and aqueous LiOH (1M, 1 mL) was added and the reaction was heated to 50°C. for 16 hours. The reaction mixture was filtered and purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound (41.3 mg, 37%) as the TFA salt. ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.31 (dd, J=2.5, 1.1 Hz, 1H),8.14-8.06 (m, 1H), 7.46-7.32 (m, 3H), 7.28-7.18 (m, 5H), 7.10 (s, 1H),5.27 (d, J=5.5 Hz, 1H), 4.62 (d, J=1.5 Hz, 1H), 4.33 (d, J=13.9 Hz, 1H),3.94-3.84 (m, 4H), 3.76-3.61 (m, 4H), 2.39 (d, J=1.6 Hz, 1H), 1.75-1.20(m, 6H), 0.77 (s, 9H); MS (ESI+) m/z 641 (M+H)⁺.

Example 181(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Into a 4 mL vial was added (2S,3R,4S,5S)-ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(Example 178C, 38.6 mg, 0.057 mmol),(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid (115 μL, 0.069mmol), and PdCl₂(dppf) (4.21 mg, 5.75 μmol) in dioxane (1 mL) to providean orange suspension. Cesium carbonate (86 μL, 0.172 mmol) in H₂O wasadded and the reaction was stirred at 85° C. for 1 hour. The solvent wasremoved under a stream of nitrogen. The residue was dissolved in 1 mLdichloromethane and extracted with H₂O (2×2 mL). The organic phase wasdried and dissolved in 3:2 tetrahydrofuran/methanol. Aqueous lithiumhydroxide monohydrate (200 μL, 1.000 mmol) was added and the reactionwas stirred overnight at 45° C. The solvent was removed under a streamof nitrogen. The residue was acidified with 2 M aqueous HCl andextracted with dichloromethane (2×2 mL). The solvent was removed under astream of nitrogen. The residue was dissolved in CH₃CN and purified byprep HPLC using HPLC TFA method 8. The desired product co-eluted withdppf ligand. The desired fractions were collected, combined andconcentrated. The crude material was dissolved in CH₃CN and repurifiedusing HPLC method AA6 (17.0 mg, 44% yield). ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.35-8.24 (m, 2H), 7.46-7.38 (m, 1H),7.38-7.29 (m, 1H), 7.26-7.14 (m, 3H), 7.07 (s, 1H), 6.43 (d, J=9.3 Hz,1H), 5.23 (s, 1H), 4.47 (s, 1H), 4.31 (d, J=13.9 Hz, 1H), 3.87 (s, 6H),3.44 (s, 3H), 2.58-2.53 (m, 1H), 1.77-1.04 (m, 6H), 0.86 (s, 9H); MS(APCI+) m/z 672.4 (M+H)⁺.

Example 182(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 149E-F-146D, substituting cyclohexanecarbonyl chloride for(S)-tetrahydrofuran-2-carboxylic acid. ¹H NMR (400 MHz, DMSO-d₆, 120°C.) δ ppm 8.00 (s, 1H), 7.75 (dd, J=2.4, 0.8 Hz, 1H), 7.10 (h, J=6.4,5.8 Hz, 2H), 6.99 (dd, J=7.1, 2.0 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 5.66(d, J=5.8 Hz, 1H), 4.62 (d, J=2.1 Hz, 1H), 4.33 (d, J=5.8 Hz, 1H), 4.22(dt, J=13.4, 0.8 Hz, 1H), 3.86 (dt, J=13.3, 0.9 Hz, 1H), 3.75 (s, 3H),3.30 (p, J=8.3 Hz, 1H), 2.54 (s, 1H), 2.29-2.15 (m, 2H), 2.06 (s, 1H),2.02-1.77 (m, 5H), 1.64 (d, J=10.2 Hz, 2H), 1.52-1.37 (m, 2H), 1.23(ddd, J=23.0, 12.9, 7.1 Hz, 6H), 1.02 (s, 11H), 0.67 (s, 1H), 0.61-0.48(m, 1H); MS (ESI+) m/z 589 (M+H)⁺.

Example 183(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 144D-Example 144F, substituting cyclohexanecarbonyl chloride for(S)-tetrahydrofuran-2-carboxylic acid in Example 144D. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 8.08 (s, 1H), 7.77 (dd, J=2.4, 0.7 Hz, 1H), 7.51(d, J=7.9 Hz, 1H), 7.26 (t, J=7.4 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 6.85(d, J=2.4 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.59 (d, J=2.1 Hz, 1H), 4.33(dd, J=6.0, 1.3 Hz, 1H), 4.25 (dt, J=13.2, 0.8 Hz, 1H), 3.98-3.90 (m,1H), 3.76 (s, 3H), 3.39-3.24 (m, 1H), 2.54 (s, 1H), 2.33-2.17 (m, 2H),2.02-1.79 (m, 3H), 1.59 (d, J=61.5 Hz, 4H), 1.36-1.04 (m, 6H), 1.00 (s,9H); MS (ESI+) m/z 627 & 629 (M+H)⁺.

Example 184(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 184A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1,2-dicarboxylate

To a mixture of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylatefrom Example 179C (100 mg, 0.248 mmol) and1-(bromomethyl)-2-methoxy-4-(trifluoromethyl)benzene (73.3 mg, 0.273mmol) in dimethyl formamide (N,N-dimethylformamide) (1.25 mL) cooling inan ice bath, potassium 2-methylpropan-2-olate (0.273 mL, 0.273 mmol)solution was added dropwise over 4 minutes. After 60 minutes, thereaction mixture was acidified with 1M aqueous HCl (0.23 mL) and warmedto ambient temperature. The mixture was diluted with water (10 mL) andextracted with dichloromethane. The extracts were loaded onto a 24 gsilica gel column and the column was eluted with a gradient of 0-65%ethyl acetate/heptanes over 20 minutes to give the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.92 (s, 1H), 7.15-7.02 (m, 4H), 6.98 (dt,J=8.0, 1.1 Hz, 1H), 6.62 (d, J=7.9 Hz, 1H), 5.66 (d, J=120.3 Hz, 1H),5.17-5.09 (m, 1H), 4.84 (d, 1H), 4.44 (d, J=1.9 Hz, 1H), 4.35 (bs, 3H),4.24 (d, 1H), 4.21 (d, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.83 (d, J=14.1 Hz,1H), 3.71 (s, 3H), 2.69 (dq, J=15.0, 7.5 Hz, 1H), 2.56-2.48 (m, 1H),2.43 (d, J=1.7 Hz, 1H), 1.12 (td, J=7.3, 5.1 Hz, 6H), 0.98 (s, 9H); MS(APCI+) m/z 592 (M+H)⁺.

Example 184B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1,2-dicarboxylatefrom Example 184A (75 mg, 0.127 mmol) in acetonitrile/water (1.24 mL,10:1) was added tetrakis(triphenylphosphine)palladium(0) (3.22 mg, 2.79μmol) and diethylamine (0.026 mL, 0.254 mmol) The mixture was stirred atambient temperature for 16 hours. Dichloromethane and water were added.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by chromatography, eluting on 12g cartridge with a gradient 0-60% ethyl acetate/heptanes over 20 minutesto yield (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrrolidine-2-carboxylate.¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.64-7.58 (m, 1H), 7.21-7.08 (m, 5H),6.94 (d, J=8.0 Hz, 1H), 4.21 (dd, J=8.1, 4.3 Hz, 1H), 4.18-4.09 (m, 3H),3.89 (dd, J=4.5, 1.7 Hz, 1H), 3.73 (s, 3H), 3.70 (d, 1H), 3.57 (t, J=7.2Hz, 1H), 3.08 (t, J=7.9 Hz, 1H), 2.69 (dq, J=15.0, 7.5 Hz, 1H), 2.60(dq, J=14.8, 7.5 Hz, 1H), 2.31 (dd, J=7.1, 1.6 Hz, 1H), 1.20 (t, J=7.1Hz, 3H), 1.17 (t, J=7.6 Hz, 3H), 0.94 (s, 9H); MS (APCI+) m/z 508(M+H)⁺.

Example 184C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrrolidine-2-carboxylatefrom Example 184B (57 mg, 0.112 mmol) in dichloromethane (0.6 mL) at 0°C. was added triethylamine (0.070 mL, 0.505 mmol) followed by additionof (S)-tetrahydro-2H-pyran-2-carbonyl chloride (28.4 mg, 0.191 mmol) asa solution in 1 mL dichloromethane. After stirring for 15 minutes, thereaction mixture was quenched with 5 mL of saturated aqueous sodiumbicarbonate. The crude organics were chromatographed using a 12 g silicagel cartridge with a gradient of 0-65% ethyl acetate/heptanes over aperiod of 20 minutes to give (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.06-7.90 (m, 1H), 7.12 (m, 3H), 7.04(d, J=1.6 Hz, 1H), 6.98 (d, J=7.5 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 5.52(s, 1H), 4.67 (s, 1H), 4.22 (d, J=13.6 Hz, 1H), 4.16 (d, J=5.7 Hz, 1H),4.10 (q, J=7.1 Hz, 2H), 3.86 (d, J=13.5 Hz, 1H), 3.72 (m, 4H), 2.74 (dt,J=15.0, 7.6 Hz, 1H), 2.63 (dt, J=15.0, 7.5 Hz, 1H), 2.40 (d, J=1.9 Hz,1H), 1.65 (m, 1H), 1.51 (m, 2H), 1.35 (m, 2H), 1.21 (t, J=7.5 Hz, 3H),1.16 (t, J=7.1 Hz, 3H), 1.00 (s, 9H); MS (APCI+) m/z 621 (M+H)⁺.

Example 184D(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 184C (57 mg, 0.092 mmol) in tetrahydrofuran (0.3 mL),methanol (0.300 mL) and water (0.300 mL) was added lithium hydroxidehydrate (27.0 mg, 0.644 mmol) and the reaction was heated at 45° C. for16 hours. The solvent was removed under a stream of nitrogen. Water (0.5mL) was added to the crude material. The mixture was acidified with 1Maqueous HCl (0.6 mL) to pH˜6, extracted once with heptane (discarded),and filtered. The precipitate was dissolved in dichloromethane, and thesolvent was evaporated in vacuo. The crude residue was chromatographedusing a 4 g silica gel cartridge with a gradient of 0-10%methanol/dichloromethane over a period of 9 minutes to give(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.20 (d, J=7.8 Hz, 1H), 7.19-6.99(m, 4H), 6.97-6.88 (d, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.51 (s, 1H), 4.55(s, 1H), 4.25 (d, J=13.9 Hz, 1H), 4.13 (d, J=6.0 Hz, 1H), 3.89 (d,J=13.8 Hz, 1H), 3.72 (m, 4H), 3.48 (bs, 2H) 2.78-2.66 (m, 1H), 2.61 (dt,J=15.0, 7.5 Hz, 1H), 2.56 (s, 1H), 1.65 (s, 1H), 1.51 (t, J=11.5 Hz,1H), 1.33 (s, 2H), 1.19 (t, J=7.5 Hz, 3H), 0.99 (s, 9H); MS (APCI+) m/z592 (M+H)⁺.

Example 185(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 185A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-ethylphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 278C (184 mg, 0.426 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (158 mg, 0.618 mmol) weredissolved in dry N,N-dimethylformamide (2.2 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (0.640 mL, 0.640 mmol) solutionwas added dropwise over 2 minutes. After 30 minutes, the mixture wasquenched with saturated aqueous NH₄Cl solution and was extracted withdichloromethane. The organic solvent was evaporated and the residue wasloaded onto a 24 g silica gel column and was eluted with 0-70% ethylacetate/heptanes over 20 minutes to give (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-ethylphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.02 (d, J=7.7 Hz, 1H), 7.75 (d, J=2.5Hz, 1H), 7.16 (s, 2H), 7.09 (s, 1H), 6.90 (d, J=2.4 Hz, 1H), 5.54 (s,1H), 4.68 (s, 1H), 4.20 (d, 1H), 4.17 (d, J=13.8 Hz, 2H), 4.09 (qd,J=7.1, 1.1 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 3.74 (s, 3H), 3.72 (m, 1H),3.40-3.24 (m, 1H), 2.70 (dp, J=30.3, 7.5 Hz, 2H), 2.41 (d, J=1.8 Hz,1H), 2.35-2.17 (m, 3H), 2.05-1.79 (m, 5H), 1.65 (d, J=12.4 Hz, 1H), 1.51(d, J=11.9 Hz, 2H), 1.32 (d, J=16.9 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H),1.14 (t, J=7.1 Hz, 3H), 1.01 (s, 9H); MS (APCI+) m/z 607 (M+H)⁺.

Example 185B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-ethylphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(205 mg, 0.338 mmol) in tetrahydrofuran (1.0 mL), methanol (1.000 mL)and water (1.000 mL) was added lithium hydroxide hydrate (99 mg, 2.365mmol) and the reaction was heated at 45° C. for 16 hours. The solventwas removed under a stream of nitrogen. Water (2 mL) was added to thecrude material. The mixture was extracted with 2×10 mL heptane(discarded), and extracted with diethyl ether. The mixture wasconcentrated, and 2 mL of water was added. The mixture was acidifiedwith 1M aqueous HCl (0.4 mL) to pH˜6, and filtered to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.14 (d, J=7.7 Hz, 1H), 7.76(d, J=2.5 Hz, 1H), 7.15 (s, 2H), 7.09 (s, 1H), 6.87 (d, J=2.4 Hz, 1H),5.54 (s, 1H), 4.60 (s, 1H), 4.23-4.16 (m, 3H), 3.81 (d, J=13.5 Hz, 1H),3.75 (s, 3H), 3.73 (bs, 2H), 3.32 (p, J=8.5 Hz, 1H), 2.78-2.69 (m, 1H),2.65 (dt, J=14.8, 7.5 Hz, 1H), 2.52 (s, 1H), 2.24 (m, 2H), 2.01-1.91 (m,3H), 1.91-1.82 (m, 1H), 1.66 (m, 1H), 1.53 (m, 2H), 1.42-1.25 (m, 3H),1.22 (t, J=7.5 Hz, 3H), 1.01 (s, 9H); MS (APCI+) m/z 579 (M+H)⁺.

Example 186(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188, substituting Intermediate 2 for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.94 (s, 1H), 7.11 (d, J=4.2 Hz, 3H), 5.44 (s, 1H),4.48-4.35 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.95 (s, 2H), 3.84-3.75 (m,2H), 3.34 (s, 1H), 2.95 (s, 1H), 2.32 (s, 3H), 2.21 (t, J=3.9 Hz, 1H),1.36 (d, J=24.9 Hz, 5H), 1.24 (t, J=7.1 Hz, 6H), 0.98 (s, 9H); MS (ESI+)m/z 418.2 (M+H)⁺.

Example 187(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-cyanopropan-2-yl)-2-methoxyphenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 187A((5-bromo-2-methoxybenzyl)oxy)(tert-butyl)dimethylsilane

5-Bromo-2-methoxyphenyl)methanol (1.89 g, 8.71 mmol) was dissolved in 25mL of dichloromethane. Imidazole (0.711 g, 10.45 mmol) was added,followed by addition of tert-butyldimethylsilyl chloride (1.378 g, 9.14mmol) in one portion. After stirring at room temperature for 30 minutes,methanol (1 mL) was added, and the reaction mixture was stirred for 5minutes. The mixture was washed with 1M aqueous HCl (3×5 mL) and brine(5 mL) and the organics were dried over sodium sulfate, filtered, andconcentrated in vacuo to give the title compound which was used withoutadditional purification. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.54 (dt,J=2.3, 1.1 Hz, 1H), 7.32-7.24 (m, 1H), 6.65 (d, J=8.6 Hz, 1H), 4.68 (d,J=1.0 Hz, 2H), 3.76 (s, 3H), 0.94 (s, 9H), 0.10 (s, 6H); MS (ESI) m/z331.0 (M+H)⁺.

Example 187B2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxyphenyl)-2-methylpropanenitrile

A 250-mL round bottom flask was charged with Example 187A (2.7 g, 8.15mmol), BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 0.507 g,0.815 mmol), and diacetoxypalladium (0.183 g, 0.815 mmol). Toluene (20mL) was added, and the suspension was sparged with N₂ for 15 minutes. Aseparate 100-mL round-bottomed flask was charged with a solution ofsodium bis(trimethylsilyl)amide (0.6 M in toluene, 20.37 mL, 12.22mmol), and isobutyronitrile (0.841 mL, 9.37 mmol) was added dropwise.After stirring for 10 minutes, the solution of deprotonated nitrile wasadded to the suspension of the remaining reagents. The flask was thenheated to 100° C. for 16 hours. The reaction flask was cooled to roomtemperature. The mixture was extracted with methyl tert-butyl etherafter diluting with saturated aqueous ammonium chloride. The organicextracts were concentrated in vacuo and purified via flashchromatography, eluting with 0:100 to 20:80 ethyl acetate:heptanes over20 minutes on a 40 g silica gel column to give the title compound. ¹HNMR (400 MHz, Chloroform-d) δ ppm 7.50 (dd, J=2.6, 1.4 Hz, 1H), 7.28(dd, J=8.5, 2.7 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 4.69 (s, 2H), 3.75 (s,3H), 1.64 (s, 6H), 0.90 (s, 9H), 0.05 (s, 6H); MS (ESI) m/z 320.0(M+H)⁺.

Example 187C2-(3-(hydroxymethyl)-4-methoxyphenyl)-2-methylpropanenitrile

Example 187B (2 g, 6.26 mmol) was dissolved in methanol (10 mL) and HCl(3M in cyclopropyl methyl ether, 0.209 mL, 0.626 mmol) was added.Stirring was continued for 10 minutes, at which point completedeprotection had occurred. The reaction was concentrated in vacuo togive the title compound, which was used without additional purification.¹H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (d, J=8.4 Hz, 2H), 6.88 (d,J=8.2 Hz, 1H), 4.70 (s, 2H), 3.87 (s, 3H), 2.16 (br s, 1H), 1.71 (s,6H); MS (ESI) m/z 188.0 (M-OH)⁺.

Example 187D 2-(3-(bromomethyl)-4-methoxyphenyl)-2-methylpropanenitrile

To 2-(3-(hydroxymethyl)-4-methoxyphenyl)-2-methylpropanenitrile (470 mg,2.290 mmol) dissolved in dichloromethane (11.4 mL) was addeddibromotriphenylphosphorane (1063 mg, 2.52 mmol) all at once, and theresulting solution was stirred at room temperature for 30 minutes. Themixture was diluted with methyl tert-butyl ether, filtered, and thefiltrate was concentrated. The residue was loaded onto a 12 g silica gelcolumn and was eluted with 0-15% methyl tert-butyl ether in heptane over15 minutes to give the title compound. ¹H NMR (400 MHz, Chloroform-d) δppm 7.48-7.32 (m, 2H), 6.93-6.84 (m, 1H), 4.56 (s, 2H), 3.91 (s, 3H),1.72 (s, 6H).

Example 187E(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-cyanopropan-2-yl)-2-methoxyphenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188, substituting Example 187D for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.26 (dd, J=8.6, 2.7 Hz, 1H), 7.08 (d, J=3.9 Hz,3H), 6.89 (d, J=2.7 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 5.51 (s, 1H),4.63-4.57 (m, 1H), 4.22 (d, J=5.9 Hz, 1H), 4.18 (d, J=12.8 Hz, 1H), 3.78(dd, J=20.3, 12.1 Hz, 3H), 3.66 (s, 3H), 2.45-2.43 (m, 1H), 2.33 (s,3H), 1.68-1.61 (m, 1H), 1.56 (d, J=5.3 Hz, 6H), 1.50 (d, J=12.4 Hz, 1H),1.31 (d, J=8.7 Hz, 4H), 0.98 (s, 9H); MS (ESI+) m/z 577 (M+H)⁺.

Example 188(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 188A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-1,2-dicarboxylate (1.44g, 3.70 mmol) (Example 129C) and1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (1.155 g, 7.39 mmol) inethyl acetate/dichloromethane(1:1) (8 mL) was addedtetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.074 mmol). Themixture was stirred at room temperature for 30 minutes. Dichloromethaneand aqueous Na₂CO₃ (2N, 2 mL) were added and the mixture was stirred for10 minutes. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by chromatographyon a 24 g silica gel cartridge, eluting with ethyl acetate in heptane ata 0-50% gradient to provide the title compound. MS (APCI+) m/z 306(M+H)⁺.

Example 188B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

To (S)-tetrahydro-2H-pyran-2-carboxylic acid (0.469 g, 3.60 mmol)(Intermediate 5) and a drop of N,N-dimethylformamide in CH₂Cl₂ (2 mL)was added oxalyl dichloride (0.831 g, 6.55 mmol) dropwise. The mixturewas stirred at room temperature for 20 minutes. The solvent was removedand fresh CH₂Cl₂ was added. The solvent was removed again. The residuewas added to CH₂Cl₂ (2 mL) and added to a mixture of Example 188A (1.0g, 3.27 mmol) and triethylamine (1.369 mL, 9.82 mmol) in CH₂Cl₂ (8 mL)cooling in an ice bath. During the addition, the temperature was keptaround 0° C. The mixture was stirred in ice bath for 20 minutes, andallowed to warm to ambient temperature. CH₂Cl₂ (20 mL) and water (10 mL)were added. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to yield the title compound, which was used inthe next step. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.94 (s, 1H), 7.11 (d,J=4.2 Hz, 3H), 5.44 (s, 1H), 4.48-4.35 (m, 2H), 4.15 (q, J=7.1 Hz, 2H),3.95 (s, 2H), 3.84-3.75 (m, 2H), 3.34 (s, 1H), 2.95 (s, 1H), 2.32 (s,3H), 2.21 (t, J=3.9 Hz, 1H), 1.36 (d, J=24.9 Hz, 5H), 1.24 (t, J=7.1 Hz,6H), 0.98 (s, 9H); MS (ESI+) m/z 418.2 (M+H)⁺.

Example 188C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To Example 188B (100 mg, 0.239 mmol) and2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (Intermediate 6) (67.8mg, 0.263 mmol) in N,N-dimethylformamide (2 mL) cooling in an ice bathwas added potassium 2-methylpropan-2-olate (0.36 mL, 1.0 M in CH₂Cl₂)dropwise. The mixture was stirred in ice bath for 20 minutes, warmed toambient temperature, and stirred for 30 minutes. Dichloromethane (10 mL)and saturated aqueous NH₄Cl (10 mL) were added and the organic layer waswashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified via chromatography on a 10 g silica gel cartridge,eluting with ethyl acetate in heptane at a 0-60% gradient to yield theintermediate, (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate,which was dissolved in methanol (2 mL) and 6 N aqueous LiOH (0.5 mL).The mixture was stirred at 45° C. for 4 hours, and the pH was adjustedto 1˜2 by adding 2N aqueous HCl. The mixture was extracted withdichloromethane, dried over MgSO₄, filtered, and concentrated.Purification via chromatography, eluting with methanol in CH₂Cl₂, 0-20%gradient, provided the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.07-8.01 (m, 1H), 7.14-7.05 (m, 4H), 6.85 (d, J=2.6 Hz, 1H), 6.72 (d,J=8.6 Hz, 1H), 5.50 (s, 1H), 4.59 (d, J=2.0 Hz, 1H), 4.22-4.10 (m, 3H),3.77 (dd, J=16.6, 12.1 Hz, 3H), 3.61 (s, 3H), 2.44 (d, J=2.0 Hz, 1H),2.32 (s, 3H), 1.70-1.29 (m, 6H), 1.17 (s, 9H), 0.97 (s, 9H); MS (ESI+)m/z 566 (M+H)⁺.

Example 189(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 188B) (100 mg, 0.239 mmol) and3-(bromomethyl)-2-methoxyquinoline [CAS#85-46-1](66.4 mg, 0.263 mmol) inN,N-dimethylformamide (2 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (40.3 mg, 0.359 mmol), (0.36 mL, 1.0 M indichloromethane) was added dropwise. The mixture was stirred in an icebath for 20 minutes, and stirred at room temperature for 30 minutes.Dichloromethane (20 mL) and saturated aqueous NH₄Cl (5 mL) were added.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography, eluting withethyl acetate in heptane, using a 0-40% gradient to give(2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxyquinolin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate,which dissolved in methanol (2 mL) and 6 M aqueous LiOH (0.5 mL). Themixture was stirred at 50° C. for 4 hours. The pH was adjusted to 1˜2 byadding 2 M aqueous HCl. The mixture was concentrated to dryness. Theresidue was purified by chromatography, eluting with ethylacetate/methanol (9:1) in heptane, at a 0-50% gradient to yield thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.12-8.06 (m, 1H), 7.66(dq, J=7.9, 1.0 Hz, 1H), 7.54 (dd, J=8.3, 7.3 Hz, 2H), 7.34 (td, J=7.2,1.2 Hz, 1H), 7.26 (q, J=1.1 Hz, 1H), 7.13 (d, J=4.6 Hz, 3H), 5.59 (d,J=9.3 Hz, 1H), 4.69-4.65 (m, 1H), 4.34 (dd, J=14.0, 1.3 Hz, 1H), 4.30(d, J=5.8 Hz, 1H), 3.97 (dd, J=14.0, 1.3 Hz, 1H), 3.91 (s, 3H), 3.77 (d,J=11.3 Hz, 1H), 3.40 (s, 2H), 2.53 (d, J=1.9 Hz, 1H), 2.32 (s, 3H),1.71-1.30 (m, 6H), 1.02 (s, 9H); MS (ESI+) m/e 561 (M+H)⁺.

Example 190(2S,3R,4S,5S)-3-tert-butyl-5-(4′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A 4 mL vial was charged with Pd(dppf)Cl₂([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 2.72 mg,0.0037 mmol, 0.1 eq) and stir bar. To this was added a stock solution ofExample 178C (0.074 M in dioxane, 500 μL, 0.037 mmol, 1.0 eq) and4-fluorophenylboronic acid (0.6 M in dioxane, 74 μL, 0.044 mmol, 1.2eq), followed by the addition of Cs₂CO₃ (1 M in water, 111 μL, 0.11mmol, 3.0 eq). The vial was capped and placed to stir at 85° C. for 2hours. The solvent was removed under a stream of nitrogen and thereaction vial was charged with tetrahydrofuran (1 mL). To this was added1 mL of a 1M aqueous solution of LiOH in 75% methanol. The reaction wasplaced to stir at 60° C. until the hydrolysis was complete. The materialwas dried in vacuo, dissolved in methanol, passed through a diatomaceousearth cartridge and washed with methanol (2×1 mL). The sample was driedin vacuo and dissolved in DMSO and filtered and purified via preparativereverse phase HPLC/MS to provide the title compound. ¹H NMR (400 MHz,120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.35-8.26 (m, 1H), 8.20-8.07 (m,1H), 7.32-7.18 (m, 7H), 7.17-7.01 (m, 1H), 5.28-5.17 (m, 1H), 4.61 (s,1H), 4.40-4.26 (m, 1H), 4.02-3.79 (m, 4H), 3.78-3.59 (m, 2H), 3.29-3.04(m, 2H), 2.44 (s, 1H), 1.76-1.11 (m, 6H), 0.80 (s, 9H); MS (APCI+) m/z659.4 (M+H)⁺.

Example 191(2S,3R,4S,5S)-3-tert-butyl-5-(3′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 191 was prepared following the general procedure used to prepareExample 190, substituting 3-chlorophenylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.37-8.26 (m, 1H), 8.21-8.11 (m, 1H), 7.53-7.37 (m, 2H),7.36-7.03 (m, 6H), 5.30-5.12 (m, 1H), 4.61 (s, 1H), 4.33 (d, J=13.9 Hz,1H), 4.00-3.82 (m, 4H), 3.71 (s, 2H), 3.29-3.05 (m, 2H), 2.45 (s, 1H),1.84-1.06 (m, 6H), 0.81 (s, 9H); MS (APCI+) m/z 675.3 (M+H)⁺.

Example 192(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 192 was prepared following the general procedure used to prepareExample 190, substituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinefor 4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.29 (s, 1H), 8.11-7.90 (m, 1H), 7.25-6.91(m, 4H), 5.45 (s, 1H), 5.43-5.31 (m, 1H), 4.71 (s, 1H), 4.34 (d, J=14.0Hz, 1H), 4.11-4.04 (m, 1H), 3.93-3.84 (m, 4H), 3.79-3.65 (m, 2H),3.36-3.03 (m, 2H), 2.67 (d, J=30.9 Hz, 2H), 2.56-2.43 (m, 2H), 2.37 (s,5H), 1.76-1.29 (m, 6H), 1.01 (s, 9H); MS (APCI+) m/z 660.4 (M+H)⁺.

Example 193(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrazol-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 193 was prepared following the general procedure used to prepareExample 190, substituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.27 (s, 1H), 8.19 (d, J=7.3 Hz, 1H), 7.62 (s, 1H), 7.40(s, 1H), 7.19 (d, J=18.7 Hz, 4H), 5.56-5.43 (m, 1H), 4.62-4.50 (m, 1H),4.29 (d, J=13.9 Hz, 1H), 3.97-3.83 (m, 7H), 3.68-3.16 (m, 4H), 1.89 (s,1H), 1.67-1.20 (m, 6H), 0.91 (s, 9H); MS (APCI+) m/z 645.4 (M+H)⁺.

Example 194 (2S,3R,4S,5S)-3-tert-butyl-5-[3′-(dimethylamino)[1,1′-biphenyl]-2-yl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 194 was prepared following the general procedure used to prepareExample 190, substituting (3-(dimethylamino)phenyl)boronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.36-8.25 (m, 1H), 8.09-8.01 (m, 1H), 7.30-7.08 (m, 5H),6.80-6.66 (m, 1H), 6.61-6.56 (m, 1H), 6.53 (d, J=7.4 Hz, 1H), 5.41 (d,J=5.7 Hz, 1H), 4.64 (s, 1H), 4.32 (d, J=14.0 Hz, 1H), 3.93-3.85 (m, 4H),3.81-3.65 (m, 2H), 3.25-3.06 (m, 2H), 2.84 (s, 6H), 2.41 (d, J=1.5 Hz,1H), 1.76-1.13 (m, 6H), 0.79 (s, 9H); MS (APCI+) m/z 684.4 (M+H)⁺.

Example 195(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2′-methyl[1,1′-biphenyl]-2-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 195 was prepared following the general procedure used to prepareExample 190, substituting o-tolylboronic acid for 4-fluorophenylboronicacid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.37-8.26(m, 1H), 8.16-8.03 (m, 1H), 7.34-7.13 (m, 7H), 7.05-6.98 (m, 1H),5.30-5.21 (m, 1H), 4.74-4.69 (m, 1H), 4.62 (s, 1H), 4.38 (d, J=13.8 Hz,1H), 4.02-3.89 (m, 4H), 3.85-3.72 (m, 2H), 3.66-3.23 (m, 2H), 2.45 (s,1H), 1.99 (s, 3H), 1.53 (d, J=67.9 Hz, 6H), 0.73 (d, J=2.5 Hz, 9H); MS(APCI+) m/z 655.4 (M+H)⁺.

Example 196 (2S,3R,4S,S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyridin-4-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 196 was prepared following the general procedure used to prepareExample 190, substituting pyridin-4-ylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.68-8.54 (m, 2H), 8.37-8.27 (m, 1H), 8.20-8.11 (m, 1H),7.40-7.02 (m, 6H), 5.28-5.17 (m, 1H), 4.65 (s, 1H), 4.37-4.30 (m, 1H),4.01-3.84 (m, 4H), 3.80-3.65 (m, 2H), 3.29-3.01 (m, 2H), 2.43 (s, 1H),1.67-1.36 (m, 6H), 0.81 (s, 9H); MS (APCI+) m/z 642.3 (M+H)⁺.

Example 197(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyrimidin-5-yl)phenyl]pyrrolidine-2-carboxylicacid

Example 197 was prepared following the general procedure used to prepareExample 190, substituting pyrimidin-5-ylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 9.18 (s, 1H), 8.72 (s, 2H), 8.42-8.30 (m, 1H), 8.30-8.16(m, 1H), 7.30 (d, J=29.9 Hz, 4H), 5.16-5.04 (m, 1H), 4.66-4.59 (m, 1H),4.33 (d, J=13.7 Hz, 1H), 4.03-3.87 (m, 4H), 3.79-3.60 (m, 2H), 3.27-2.99(m, 2H), 2.47 (s, 1H), 1.82-1.12 (m, 6H), 0.82 (s, 9H); MS (APCI+) m/z643.4 (M+H)⁺.

Example 198(2S,3R,4S,5S)-3-tert-butyl-5-[2-(furan-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 198 was prepared following the general procedure used to prepareExample 190, substituting furan-3-ylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.32-8.28 (m, 1H), 8.21-8.11 (m, 1H), 7.76-7.66 (m, 1H),7.62-7.55 (m, 1H), 7.30-7.12 (m, 4H), 6.56 (dd, J=1.8, 0.9 Hz, 1H),5.68-5.40 (m, 1H), 4.63 (s, 1H), 4.30 (d, J=14.0 Hz, 1H), 4.06-3.93 (m,1H), 3.92-3.81 (m, 4H), 3.75-3.61 (m, 1H), 3.11-3.03 (m, 2H), 2.47 (s,1H), 1.74-1.23 (m, 6H), 0.92 (s, 9H); MS (APCI+) m/z 631.3 (M+H)⁺.

Example 199(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrrol-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 199 was prepared following the general procedure used to prepareExample 190, substituting1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.29 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.30-7.24 (m, 1H),7.21-7.07 (m, 3H), 6.77-6.72 (m, 1H), 6.68-6.63 (m, 1H), 6.08 (t, J=2.3Hz, 1H), 5.71 (s, 1H), 4.62 (s, 1H), 4.29 (d, J=14.0 Hz, 1H), 3.88 (s,4H), 3.74-3.34 (m, 5H), 3.18-2.90 (m, 2H), 2.44 (d, J=1.6 Hz, 1H),1.71-1.24 (m, 6H), 0.92 (s, 9H); MS (APCI+) m/z 644.4 (M+H)⁺.

Example 200(2S,3R,4S,5S)-3-tert-butyl-5-(2′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 200 was prepared following the general procedure used to prepareExample 190, substituting 2-chlorophenylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.29 (d, J=12.5 Hz, 1H), 8.17-8.11 (m, 1H), 7.57-7.49 (m,2H), 7.45-7.38 (m, 2H), 7.27 (s, 2H), 7.16-7.02 (m, 2H), 4.69-4.52 (m,1H), 4.46-4.26 (m, 1H), 4.01-3.82 (m, 5H), 3.81-3.59 (m, 2H), 3.33-2.92(m, 2H), 2.46 (s, 1H), 1.85-1.13 (m, 6H), 0.82-0.66 (m, 9H); MS (APCI+)m/z 675.4 (M+H)⁺.

Example 201(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[3′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylicacid

Example 201 was prepared following the general procedure used to prepareExample 190, substituting (3-(trifluoromethoxy)phenyl)boronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.37-8.27 (m, 1H), 8.25-8.10 (m, 1H), 7.58 (t, J=8.0 Hz,1H), 7.43-7.24 (m, 4H), 7.24-7.15 (m, 1H), 7.15-7.07 (m, 2H), 5.26 (s,1H), 4.64 (s, 1H), 4.32 (d, J=13.9 Hz, 1H), 3.96-3.85 (m, 4H), 3.83-3.50(m, 2H), 3.26-2.94 (m, 2H), 2.43 (s, 1H), 1.79-1.13 (m, 6H), 0.78 (s,9H); MS (APCI+) m/z 725.4 (M+H)⁺.

Example 202(2S,3R,4S,5S)-3-tert-butyl-5-(4′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 202 was prepared following the general procedure used to prepareExample 190, substituting 4-chlorophenylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.32 (s, 1H), 8.17-8.09 (m, 1H), 7.53-7.44 (m, 2H),7.33-7.21 (m, 5H), 7.18-7.06 (m, 1H), 5.26-5.19 (m, 1H), 4.69-4.58 (m,1H), 4.33 (d, J=13.8 Hz, 1H), 3.99-3.83 (m, 4H), 3.79-3.61 (m, 2H),3.20-2.94 (m, 2H), 2.43 (d, J=1.4 Hz, 1H), 1.80-1.09 (m, 6H), 0.81 (s,9H); MS (APCI+) m/z 675.3 (M+H)⁺.

Example 203(2S,3R,4S,5S)-5-[2-(2H-1,3-benzodioxol-5-yl)phenyl]-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 203 was prepared following the general procedure used to prepareExample 190, substituting benzo[d][1,3]dioxol-5-ylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.37-8.26 (m, 1H), 8.21-8.06 (m, 1H), 7.26-7.15 (m, 3H),7.15-7.07 (m, 1H), 6.93 (d, J=7.9 Hz, 1H), 6.76-6.73 (m, 1H), 6.69 (dd,J=7.9, 1.7 Hz, 1H), 5.99 (s, 2H), 5.30 (d, J=5.6 Hz, 1H), 4.60 (s, 1H),4.33 (d, J=13.8 Hz, 1H), 3.94-3.87 (m, 4H), 3.85-3.62 (m, 2H), 3.22-2.97(m, 2H), 2.47-2.42 (m, 1H), 1.78-1.08 (m, 6H), 0.83 (s, 9H); MS (APCI+)m/z 685.4 (M+H)⁺.

Example 204(2S,3R,4S,5S)-3-tert-butyl-5-(2′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 204 was prepared following the general procedure used to prepareExample 190, substituting 2-fluorophenylboronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.30 (s, 1H), 8.20-8.05 (m, 1H), 7.54-7.40 (m, 1H),7.34-7.07 (m, 7H), 5.10 (s, 1H), 4.63 (s, 1H), 4.35 (d, J=14.0 Hz, 1H),3.97-3.86 (m, 4H), 3.77-3.62 (m, 2H), 3.35-3.15 (m, 2H), 2.43 (s, 1H),1.77-1.11 (m, 6H), 0.78 (s, 9H); MS (APCI+) m/z 659.4 (M+H)⁺.

Example 205(2S,3R,4S,5S)-3-tert-butyl-5-[2-(6-methoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 205 was prepared following the general procedure used to prepareExample 190, substituting2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.36-8.28 (m, 1H), 8.17-8.12 (m, 1H), 8.02 (d, J=2.7 Hz,1H), 7.60 (dd, J=8.5, 2.5 Hz, 1H), 7.34-7.21 (m, 3H), 7.18-7.09 (m, 1H),6.87 (d, J=8.5 Hz, 1H), 5.34-5.09 (m, 1H), 4.62 (s, 1H), 4.33 (d, J=13.8Hz, 1H), 3.95-3.84 (m, 7H), 3.82-3.58 (m, 2H), 3.27-3.00 (m, 2H), 2.45(s, 1H), 1.80-1.18 (m, 6H), 0.82 (s, 9H); MS (APCI+) m/z 672.4 (M+H)⁺.

Example 206(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[4′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylicacid

Example 206 was prepared following the general procedure used to prepareExample 190, substituting (4-(trifluoromethoxy)phenyl)boronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.35-8.25 (m, 1H), 8.18-8.06 (m, 1H), 7.43-7.31 (m, 4H),7.31-7.19 (m, 3H), 7.16-7.07 (m, 1H), 5.24-5.12 (m, 1H), 4.64-4.57 (m,1H), 4.33 (d, J=13.7 Hz, 1H), 3.95-3.87 (m, 4H), 3.86-3.52 (m, 2H),3.33-3.00 (m, 2H), 2.46-2.37 (m, 1H), 1.49 (d, J=63.4 Hz, 6H), 0.78 (s,9H); MS (APCI+) m/z 725.4 (M+H)⁺.

Example 207(2S,3R,4S,5S)-3-tert-butyl-5-(4′-cyano[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 207 was prepared following the general procedure used to prepareExample 190, substituting (4-cyanophenyl)boronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.34-8.27 (m, 1H), 8.21-8.14 (m, 1H), 7.85 (d, J=8.1 Hz,2H), 7.46 (d, J=8.1 Hz, 2H), 7.36-7.18 (m, 3H), 7.17-7.09 (m, 1H),5.30-5.00 (m, 1H), 4.68-4.57 (m, 1H), 4.39-4.26 (m, 1H), 3.96-3.84 (m,4H), 3.81-3.55 (m, 2H), 3.27-2.95 (m, 2H), 2.43 (s, 1H), 1.83-1.15 (m,6H), 0.80 (s, 9H); MS (APCI+) m/z 666.4 (M+H)⁺.

Example 208(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-{2-[6-(trifluoromethyl)pyridin-3-yl]phenyl}pyrrolidine-2-carboxylicacid

Example 208 was prepared following the general procedure used to prepareExample 190, substituting (6-(trifluoromethyl)pyridin-3-yl)boronic acidfor 4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.64 (s, 1H), 8.32 (d, J=2.2 Hz, 1H),8.28-8.20 (m, 1H), 8.02-7.87 (m, 2H), 7.39-7.29 (m, 2H), 7.29-7.15 (m,2H), 5.20-4.96 (m, 1H), 4.61 (s, 1H), 4.34 (d, J=13.8 Hz, 1H), 3.99-3.83(m, 4H), 3.78-3.60 (m, 2H), 3.31-2.99 (m, 2H), 2.46 (s, 1H), 1.83-1.12(m, 6H), 0.79 (s, 9H); MS (APCI+) m/z 710.4 (M+H)⁺.

Example 209(2S,3R,4S,5S)-3-tert-butyl-5-[2-(5-ethoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 209 was prepared following the general procedure used to prepareExample 190, substituting (5-ethoxypyridin-3-yl)boronic acid for4-fluorophenylboronic acid. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1(v/v)) δ ppm 8.38-8.23 (m, 2H), 8.18-7.96 (m, 2H), 7.36-7.03 (m, 5H),5.27-5.20 (m, 1H), 4.66 (s, 1H), 4.30 (s, 1H), 4.20-4.00 (m, 2H), 3.90(s, 4H), 3.78-3.57 (m, 2H), 3.15-2.94 (m, 2H), 2.43 (s, 1H), 1.82-1.37(m, 6H), 1.33 (t, J=7.0 Hz, 3H), 0.81 (s, 9H); MS (APCI+) m/z 685.5(M+H)⁺.

Example 210(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 210A (E)-ethyl 2-((naphthalen-2-ylmethylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (1.117 g, 8.00 mmol) and magnesiumsulfate (1.541 g, 12.81 mmol) were suspended in dichloromethane (10.67mL) and the suspension was treated with triethylamine (1.116 mL, 8.00mmol). The mixture stirred at room temperature for 1 hour, and2-naphthaldehyde (1.0 g, 6.40 mmol) was added. The mixture was stirredat room temperature for 20 hours. The solid material was removed viafiltration and the filtrate was washed with water (quick wash twice) andbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.03 (dt, J=8.7, 1.0 Hz, 1H), 8.96 (d, J=1.4 Hz, 1H), 8.07-7.85 (m, 3H),7.64-7.50 (m, 3H), 4.52 (d, J=1.2 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H),1.25-1.10 (t, 3H); MS (ESI⁺) m/z 242.2 (M+H)⁺.

Example 210B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(naphthalen-2-yl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.063 g, 0.084 mmol) and copper (I) triflate dimer, benzene complex(0.016 g, 0.032 mmol) were dissolved in tetrahydrofuran (16.47 mL) thathad been sparged with a N₂ stream for 4 hours. The resulting solutionwas stirred for 1.5 hours at room temperature. (E)-ethyl2-((naphthalen-2-ylmethylene)amino)acetate (1.55 g, 6.42 mmol) intetrahydrofuran (1 mL) was added after cooling to <5° C. in an ice waterbath. Potassium 2-methylpropan-2-olate (0.064 mL, 0.064 mmol) was addeddropwise, followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene(0.830 g, 6.42 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete, the mixture wasstirred for 15 minutes at the same temperature. The reaction mixture wasdiluted with methyl tert-butyl ether (30 mL) and stirred with 30 mL ofsaturated aqueous ammonium chloride at room temperature for 15 minutes.The organic layer was washed with saturated aqueous sodium bicarbonateand brine, dried over sodium sulfate, and filtered. The filtrate wasconcentrated and the residue was purified by flash chromatography (0 to30% ethyl acetate in heptane) to provide the title compound. ¹H NMR (400MHz, Chloroform-d) δ ppm 7.92 (dd, J=8.1, 1.3 Hz, 1H), 7.85 (dd, J=8.3,3.4 Hz, 2H), 7.63 (ddd, J=8.2, 6.6, 1.4 Hz, 1H), 7.61-7.51 (m, 2H),7.53-7.43 (m, 1H), 5.39 (dd, J=6.0, 2.5 Hz, 1H), 5.18 (dd, J=10.7, 5.9Hz, 1H), 4.44-4.32 (m, 2H), 3.93 (t, J=7.7 Hz, 1H), 3.45 (t, J=9.9 Hz,1H), 3.15 (dd, J=7.2, 2.4 Hz, 1H), 1.40 (td, J=7.2, 0.6 Hz, 3H), 1.16(s, 9H); MS (ESI⁺) m/z 371.3

Example 210C(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure describedfrom Example 88A-H, substituting Example 210B for Core 5, andIntermediate 5 for (S)-tetrahydrofuran-2-carboxylic acid, respectively.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.30 (s, 1H), 8.21-8.07 (m, 2H),7.91-7.67 (m, 2H), 7.51 (s, 3H), 6.83 (s, 1H), 6.32 (s, 1H), 4.66 (s,1H), 4.51 (d, J=6.1 Hz, 1H), 4.20 (d, J=13.9 Hz, 1H), 3.71 (s, 3H), 3.62(s, 1H), 3.44 (s, 1H), 2.51 (s, 1H), 2.24 (s, 1H), 1.51 (s, 4H), 1.08(s, 9H), 0.74 (s, 2H); MS (ESI+) m/z 615 (M+H)⁺.

Example 211(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 88A-H, substituting Example 210B for Core 5, Intermediate 6 forIntermediate 8, and Intermediate 5 for (S)-tetrahydrofuran-2-carboxylicacid, respectively. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31 (d, J=7.3 Hz,1H), 8.15 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.2 Hz,1H), 7.57-7.51 (m, 1H), 7.44 (dt, J=15.3, 7.7 Hz, 2H), 7.01 (dd, J=8.5,2.6 Hz, 1H), 6.63-6.55 (m, 2H), 6.20 (s, 1H), 4.66 (s, 1H), 4.41 (dd,J=6.2, 1.5 Hz, 1H), 4.01 (d, J=12.4 Hz, 1H), 3.59 (d, J=12.4 Hz, 1H),3.52 (d, J=18.8 Hz, 1H), 3.48 (s, 3H), 3.30 (s, 1H), 2.52 (s, 1H), 1.51(d, J=35.5 Hz, 4H), 1.08 (s, 9H), 1.04 (s, 9H); MS (ESI+) m/z 602(M+H)⁺.

Example 212(2S,3R,4S,5S)-5-(1-benzofuran-7-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 212A (E)-ethyl 2-((benzofuran-7-ylmethylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (1.089 g, 7.80 mmol) and magnesiumsulfate (1.502 g, 12.48 mmol) were suspended in dichloromethane (10.40mL) and the suspension was treated with triethylamine (1.087 mL, 7.80mmol). The mixture was stirred at room temperature for 1 hour beforebenzofuran-7-carbaldehyde (0.94 g, 6.24 mmol) in 1 mL of dichloromethanewas added. The reaction mixture was stirred at room temperature for 20hours. The solid material was removed via filtration and the filtratewas washed with water (quick wash twice) and brine, dried over sodiumsulfate, filtered, and concentrated to give the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.80 (d, J=1.5 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H),7.77 (ddd, J=12.1, 7.6, 1.2 Hz, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.03 (d,J=2.2 Hz, 1H), 4.50 (d, J=1.3 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 1.21 (t,J=7.1 Hz, 3H); MS (ESI⁺) m/z 232.2 (M+H)⁺.

Example 212B (2S,3R,4S,5S)-ethyl5-(benzofuran-7-yl)-3-(tert-butyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.061 g, 0.081 mmol) and copper (I) triflate dimer, benzene complex(0.016 g, 0.031 mmol) were dissolved in tetrahydrofuran (15.97 mL) thathad been sparged with a N₂ stream for 4 hours. The resulting solutionwas stirred for 1.5 hours at room temperature, and (E)-ethyl2-((benzofuran-7-ylmethylene)amino)acetate (1.44 g, 6.23 mmol) intetrahydrofuran (1 mL) was added after cooling to <5° C. in an ice waterbath. Potassium 2-methylpropan-2-olate (0.062 mL, 0.062 mmol) was addeddropwise, followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene(0.804 g, 6.23 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete, the mixture wasstirred for 15 minutes at the same temperature. The mixture was dilutedwith methyl tert-butyl ether (30 mL) and stirred with 30 mL of saturatedaqueous ammonium chloride at room temperature for 15 minutes. Theorganic layer was washed with saturated aqueous sodium bicarbonate andbrine, dried over sodium sulfate, and filtered. The filtrate wasconcentrated and the residue was purified by flash chromatography (0 to30% ethyl acetate in heptane) to give the title compound. ¹H NMR (400MHz, Chloroform-d) δ ppm 7.68 (d, J=2.2 Hz, 1H), 7.58 (dd, J=7.0, 1.9Hz, 1H), 7.27 (dd, J=9.4, 7.1 Hz, 2H), 6.82 (d, J=2.2 Hz, 1H), 5.46 (dd,J=5.7, 2.3 Hz, 1H), 4.90 (dd, J=12.0, 5.7 Hz, 1H), 4.36 (qd, J=7.2, 1.3Hz, 2H), 3.91 (t, J=7.8 Hz, 1H), 3.64 (d, J=11.1 Hz, 1H), 2.98 (dd,J=7.0, 2.3 Hz, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.14 (s, 9H); MS (ESI⁺) m/z361.1 (M+H)⁺.

Example 212C(2S,3R,4S,5S)-5-(1-benzofuran-7-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure describedfrom Example 88A-H, substituting Example 212B for Core 5, Intermediate 5for (S)-tetrahydrofuran-2-carboxylic acid, respectively. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.26-8.17 (m, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.78 (d,J=2.2 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 6.97 (d,J=2.4 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.06 (s, 2H), 4.59 (s, 1H), 4.40(dd, J=6.5, 2.7 Hz, 1H), 4.29 (d, J=13.7 Hz, 1H), 3.86 (d, J=13.7 Hz,1H), 3.82 (s, 3H), 3.65 (d, J=13.6 Hz, 2H), 2.53 (t, J=3.1 Hz, 1H),1.67-1.27 (m, 6H), 1.03 (s, 9H); MS (ESI+) m/z 605 (M+H)⁺.

Example 213(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(2-methylpropyl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid oxane-2-carbonyl]pyrrolidine-2-carboxylic acid Example 213A(2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isobutylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl5-(2-bromophenyl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(Example 178C, 174 mg, 0.259 mmol), isobutylboronic acid (52.8 mg, 0.518mmol) and potassium carbonate (107 mg, 0.777 mmol) were suspended intoluene (2.5 mL). The reaction was purged with nitrogen for 2 minutes,and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.58mg, 0.013 mmol) was added. The reaction was capped and heated at 110° C.for 4 hours. The solvent was reduced under a stream of nitrogen and thecrude material was purified using a 10 g silica gel cartridge with agradient of 5-100% ethyl acetate/heptanes over 20 minutes to give thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 8.00 (dd,J=7.7, 1.4 Hz, 1H), 7.22 (s, 1H), 7.13-6.97 (m, 3H), 5.48 (s, 1H), 4.71(s, 1H), 4.40-4.28 (m, 1H), 4.25 (d, J=13.8 Hz, 1H), 4.21 (d, J=5.6 Hz,1H), 4.08 (qd, J=7.1, 3.3 Hz, 2H), 3.94 (d, J=13.6 Hz, 1H), 3.87 (s,1H), 3.84 (s, 3H), 3.78 (d, J=13.8 Hz, 1H), 3.73 (d, J=12.9 Hz, 2H),2.55 (d, J=7.0 Hz, 1H), 2.43 (d, J=1.8 Hz, 1H), 1.94 (td, J=15.7, 14.3,5.8 Hz, 1H), 1.66 (s, 1H), 1.52 (d, J=12.1 Hz, 1H), 1.36 (s, 3H), 1.14(t, J=7.1 Hz, 3H), 1.02 (d, J=2.0 Hz, 9H), 0.93 (t, J=6.4 Hz, 6H); MS(APCI+) m/z 649 (M+H)⁺.

Example 213B(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(2-methylpropyl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 213A (160 mg, 0.247 mmol) was dissolved in methanol (822 μL) andtetrahydrofuran (822 μL). A solution of lithium hydroxide (56 mg, 2.338mmol) in water (822 μL) was added. The reaction was heated at 45° C. for16 hours. The solvent was reduced in volume, and acidified with 1Maqueous HCl to pH˜3. The reaction was extracted with dichloromethane.The solvent was removed and the crude material was purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (dq,J=2.0, 1.0 Hz, 1H), 8.06 (dd, J=7.6, 1.5 Hz, 1H), 7.20 (d, J=2.4 Hz,1H), 7.06 (q, J=8.8, 7.1 Hz, 3H), 5.50 (s, 1H), 4.67 (d, J=1.7 Hz, 1H),4.29 (d, J=13.9 Hz, 1H), 4.21 (d, J=5.7 Hz, 1H), 4.07-3.97 (m, 1H), 3.86(s, 3H), 3.84-3.79 (m, 1H), 3.78-3.70 (m, 1H), 3.18 (d, J=6.3 Hz, 1H),2.53 (dd, J=7.1, 4.0 Hz, 2H), 2.49 (d, J=1.7 Hz, 1H), 1.91 (dd, J=13.3,6.8 Hz, 1H), 1.69-1.61 (m, 1H), 1.54 (q, J=11.5 Hz, 1H), 1.35 (d, J=11.8Hz, 3H), 1.03 (s, 9H), 1.00 (d, J=3.3 Hz, 1H), 0.92 (t, J=6.8 Hz, 6H);MS (ESI+) m/z 621 (M+H)⁺.

Example 214(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(6-methoxypyridine-2-sulfonyl)pyrrolidine-2-carboxylicacid Example 214A 6-fluoropyridine-2-sulfonyl chloride

Di-n-butylmagnesium (1 M in tetrahydrofuran) (3.17 mL, 3.17 mmol) andn-butyllithium (1.6 M in heptanes) (1.979 mL, 3.17 mmol) were combinedto give a suspension. To this cooled solution was added dropwise asolution of 2-bromo-6-fluoropyridine (1.393 g, 7.92 mmol) intetrahydrofuran (8 mL), keeping the internal temperature below −10° C.The reaction was stirred at −10° C. for 1 hour. The solution was addeddropwise via cannula to a cooled solution of sulfuryl chloride (16 mL,16.00 mmol) as a 1 M solution in dichloromethane while stirring in a dryice/acetone bath keeping the internal temperature around −10° C. Thesolvent was reduced in volume and the material was filtered and washedwith heptanes to give the title compound. MS (APCI+) m/z 177 (M+H)⁺.

Example 214B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)-1-((6-fluoropyridin-2-yl)sulfonyl)pyrrolidine-2-carboxylate

To a solution of Example 149C (50 mg, 0.099 mmol) and pyridine (1 mL)and 1 mL of dichloromethane was added dropwise a solution of6-fluoropyridine-2-sulfonyl chloride (Example 214A, 50 mg, 0.256 mmol)in dichloromethane. After 45 minutes, the solvent was reduced under astream of nitrogen. The organics were washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude material waspurified using a 25 g silica gel cartridge with a gradient of 5-100%ethyl acetate/heptanes to give the title compound. ¹H NMR (501 MHz,Chloroform-d) δ ppm 7.84-7.71 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.37-7.30(m, 1H), 7.11-7.07 (m, 2H), 7.07-7.02 (m, 1H), 6.83 (dt, J=8.2, 4.1 Hz,1H), 6.81-6.78 (m, 1H), 6.06 (d, J=5.6 Hz, 1H), 5.00 (d, J=2.3 Hz, 1H),4.28-4.15 (m, 4H), 3.85-3.79 (m, 5H), 3.28 (q, J=8.4 Hz, 1H), 2.65 (d,J=2.1 Hz, 1H), 2.32-2.14 (m, 1H), 2.12-1.94 (m, 3H), 1.94-1.80 (m, 2H),1.24 (t, J=7.1 Hz, 3H), 1.17 (s, 9H), 1.02-0.93 (m, 1H), 0.93-0.83 (m,2H), 0.59-0.48 (m, 1H); MS (APCI+) m/z 666 (M+H)⁺.

Example 214C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(6-methoxypyridine-2-sulfonyl)pyrrolidine-2-carboxylicacid

Example 214B (61 mg, 0.092 mmol) was dissolved in methanol (0.500 mL)and tetrahydrofuran (0.5 mL). A solution of 2 M aqueous lithiumhydroxide (0.458 mL, 0.916 mmol) was added. The reaction was heated at45° C. for 16 hours. The solvent was removed and the reaction wasacidified with 0.458 mL of 2 M aqueous HCl. The reaction was dilutedwith dichloromethane and the organics were purified using a 10 g silicagel cartridge with an ethyl acetate/ethanol/heptanes solvent system togive the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.71 (s, 1H),7.93-7.80 (m, 2H), 7.74 (d, J=2.4 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.06(dd, J=7.8, 5.3 Hz, 2H), 6.98-6.88 (m, 2H), 6.78 (d, J=2.4 Hz, 1H), 5.81(d, J=6.1 Hz, 1H), 4.48 (d, J=3.5 Hz, 1H), 4.22 (dd, J=6.2, 2.1 Hz, 1H),4.17 (d, J=13.4 Hz, 1H), 3.87 (s, 3H), 3.74 (d, J=13.4 Hz, 1H), 3.69 (s,3H), 3.28-3.18 (m, 2H), 2.42 (dd, J=3.6, 2.0 Hz, 1H), 2.15 (tdd, J=7.8,5.7, 2.4 Hz, 2H), 2.01 (td, J=8.6, 4.5 Hz, 1H), 1.96-1.76 (m, 4H), 0.89(s, 9H), 0.86-0.76 (m, 1H), 0.73-0.61 (m, 1H), 0.56 (qd, J=5.5, 2.6 Hz,1H); MS (APCI+) m/z 650 (M+H)⁺.

Example 215(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 215A 1-(4-methoxyphenyl)cyclobutanol

(4-Methoxyphenyl)magnesium bromide (56.9 mL, 28.5 mmol, 0.5 M intetrahydrofuran) solution was cooled to −78° C. before dropwise additionof cyclobutanone (2.239 mL, 30.0 mmol) via syringe. After the additionwas complete, the mixture was warmed to ambient temperature and quenchedwith saturated aqueous ammonium chloride (10 mL). The mixture wasdiluted with methyl tert-butyl ether (20 mL) and the layers wereseparated. The organic layer was washed with saturated aqueous ammoniumchloride (20 mL) and brine (20 mL), dried over sodium sulfate, filtered,and concentrated to provide the title compound which was used withoutadditional purification. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.45 (d,J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 3.84 (s, 3H), 2.57 (dddd, J=12.4,6.5, 2.8, 1.7 Hz, 2H), 2.43-2.27 (m, 2H), 2.18-1.89 (m, 2H), 1.76-1.60(m, 1H).

Example 215B 1-methoxy-4-(1-methylcyclobutyl)benzene

Example 215A (3 g, 16.83 mmol) was dissolved in dichloromethane (84 mL)and the resulting solution was cooled to −78° C. in a dry ice acetonebath. Titanium(IV) chloride (neat, 3.69 mL, 33.7 mmol) was added viasyringe and the solution was stirred for 1 hour at the same temperaturebefore the addition of dimethylzinc (50.5 mL, 50.5 mmol) solution slowlyas a 1 M solution in heptanes. After the addition was complete, thereaction flask was warmed to ambient temperature before pouring into 300mL of ice in a beaker while stirring vigorously. The resultingsuspension was diluted with dichloromethane (100 mL) and stirred for 5minutes before filtering through diatomaceous earth and washing theorganic layer with brine (50 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated to provide the titlecompound, which was used without additional purification. ¹H NMR (500MHz, Chloroform-d) δ ppm 7.14 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H),3.84 (s, 3H), 2.40 (qd, J=9.4, 8.9, 2.1 Hz, 2H), 2.21-2.04 (m, 3H),1.92-1.81 (m, 1H), 1.48 (s, 3H).

Example 215C 2-methoxy-5-(1-methylcyclobutyl)benzaldehyde

Example 215B (3 g, 17.02 mmol) was dissolved in 110 mL ofdichloromethane, and the resulting solution was cooled to <0° C. in anice brine bath. After addition of dichloro(methoxy)methane (1.70 mL,18.7 mmol), titanium tetrachloride (2.065 mL, 18.72 mmol) was addeddropwise as a solution in 10 mL of dichloromethane over 2 minutes,maintaining an internal temperature<5° C. After 15 minutes at the sametemperature, thin layer chromatography indicated complete conversion.The resulting solution was quenched with 40 mL of water, the layers wereseparated, and the organic layer was concentrated and loaded onto an 80g silica gel column, eluting with 0:100 to 15:85 ethyl acetate:heptanesover 20 minutes to provide the title compound. ¹H NMR (400 MHz,Chloroform-d) δ ppm 10.49 (d, J=1.0 Hz, 1H), 7.67 (dd, J=2.6, 0.9 Hz,1H), 7.40 (ddd, J=8.6, 2.6, 1.0 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 3.94(d, J=0.9 Hz, 3H), 2.37 (td, J=10.3, 9.7, 7.2 Hz, 2H), 2.19-2.01 (m,3H), 1.89-1.73 (m, 1H), 1.46 (s, 3H); MS (ESI+) m/z=205.1 (M+H)⁺.

Example 215D (2-methoxy-5-(1-methylcyclobutyl)phenyl)methanol

To 2-methoxy-5-(1-methylcyclobutyl)benzaldehyde (1.0 g, 4.90 mmol) inethanol (10 mL) cooling in an ice bath, sodium borohydride (0.204 g,5.39 mmol) was added in portions. The mixture was stirred in an ice bathfor 30 minutes, saturated aqueous NH₄Cl (2 mL) was added, and thesolvent was removed under reduced pressure. The residue was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganics were washed with brine, dried over sodium sulfate, filtered,and concentrated to give the title compound. MS (APCI+) m/z 207 (M+H)⁺.

Example 215E 2-(bromomethyl)-1-methoxy-4-(1-methylcyclobutyl)benzene

To triphenylphosphine (2365 mg, 9.02 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (1605 mg,9.02 mmol) in portions. The mixture was stirred for 30 minutesmaintaining an internal temperature<10° C., and(2-methoxy-5-(1-methylcyclobutyl)phenyl)methanol (930 mg, 4.51 mmol) indichloromethane (2 mL) was added slowly at <10. The mixture stirred inan ice bath for 1 hour. Saturated aqueous NH₄Cl (2 mL) was added and theorganic layer was washed with saturated aqueous sodium bicarbonate andbrine, dried over sodium sulfate, filtered, and concentrated. Theresidue was purified via chromatography, eluting with ethyl acetate inheptane at a 0-40% gradient to give the title compound. ¹H NMR (501 MHz,Chloroform-d) δ ppm 7.17-7.11 (m, 2H), 6.84 (s, 1H), 4.60 (s, 2H), 3.91(s, 3H), 2.40-2.30 (m, 2H), 2.16-1.98 (m, 3H), 1.87-1.77 (m, 1H), 1.46(d, J=0.7 Hz, 3H).

Example 215F(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To Example 188B (70 mg, 0.168 mmol) and Example 215E (54.2 mg, 0.201mmol) in N,N-dimethylformamide (2 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (0.25 mL, 1.0 M in tetrahydrofuran) was addeddropwise. The mixture was stirred in ice bath for 20 minutes, andstirred at room temperature for 30 minutes. Dichloromethane (15 mL) andsaturated aqueous NH₄Cl (5 mL) were added. The organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified via chromatography, eluting with ethyl acetate in heptane,0-40% gradient to yield ester of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(1-methylcyclobutyl)benzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate,which dissolved in methanol (2 mL) and 6N aqueous LiOH (0.5 mL). Themixture was stirred at 45° C. for 4 hours. The solvent was removed andthe residue was adjusted pH to 1˜2 by adding 2N aqueous HCl. The mixturewas extracted with dichloromethane (10 mL×3). The combined organics werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified via chromatography, eluting with ethylacetate/methanol (9:1) in heptane at 0-60% to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.07-8.00 (m, 1H), 7.08 (d,J=4.1 Hz, 3H), 6.93 (dd, J=8.4, 2.5 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H),6.64 (d, J=2.5 Hz, 1H), 5.50 (s, 1H), 4.59 (d, J=2.1 Hz, 1H), 4.19 (d,J=6.0 Hz, 1H), 4.15 (d, J=12.5 Hz, 1H), 3.81 (d, J=12.6 Hz, 1H),3.78-3.72 (m, 1H), 3.62 (s, 3H), 3.37 (s, 1H), 3.19 (s, 1H), 2.45 (d,J=2.0 Hz, 1H), 2.32 (s, 3H), 2.17 (qd, J=10.3, 8.7, 4.5 Hz, 2H),2.07-1.89 (m, 4H), 1.78-1.69 (m, 1H), 1.65 (d, J=13.6 Hz, 1H), 1.49 (t,J=12.2 Hz, 1H), 1.37 (dd, J=21.2, 9.3 Hz, 2H), 1.30 (s, 3H), 1.25 (d,J=5.8 Hz, 1H), 0.97 (s, 9H); MS (ESI+) m/z 578.1 (M+H)⁺.

Example 216(2S,3R,4S,5S)-3-tert-butyl-5-(2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

(2S,3R,4S,5S)-Ethyl5-(benzofuran-7-yl)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate(Example 212, 55 mg, 0.087 mmol) in tetrahydrofuran (1.5 mL) was addedto Ra-Ni 2800, water slurry (11.34 mg, 0.087 mmol) in a 5 mL Barnsteadreactor. The reactor was purged with argon for 5 minutes and stirredunder 50 psi of hydrogen at 50° C. for 10 hours. The mixture was cooleddown and filtered through a polypropylene membrane. The solvent wasremoved to yield (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2,3-dihydrobenzofuran-7-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate,which was dissolved in methanol (1.5 mL) and 6 N aqueous LiOH (0.5 mL)and stirred at 50° C. for 4 hours. The pH was adjusted to 1˜2 by adding2 M aqueous HCl. The mixture was concentrated to dryness. Purificationby chromatography on a 12 g silica gel cartridge, eluting with ethylacetate/methanol (9:1) in heptane using a 0-60% gradient gave the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (d, J=2.0 Hz, 1H), 7.69(d, J=7.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.00 (d, J=7.3 Hz, 1H), 6.69(t, J=7.5 Hz, 1H), 5.60 (s, 1H), 4.51-4.48 (m, 1H), 4.47-4.42 (m, 1H),4.42-4.37 (m, 1H), 4.37-4.33 (m, 1H), 4.23 (dd, J=6.6, 3.0 Hz, 1H), 4.04(d, J=13.9 Hz, 1H), 3.90 (s, 3H), 3.83-3.76 (m, 1H), 3.17-3.09 (m, 2H),2.99 (dd, J=16.2, 7.9 Hz, 4H), 1.67 (d, J=13.0 Hz, 1H), 1.56-1.31 (m,4H), 1.25 (s, 1H), 0.98 (s, 9H); MS (ESI+) m/z 607.2 (M+1)⁺.

Example 217(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopropyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 217A 5-cyclopropyl-2-methoxynicotinaldehyde

5-Bromo-2-methoxynicotinaldehyde (4 gg, 18.52 mmol) in 1,4-dioxane (40mL) was degassed with nitrogen for 5 minutes, and cyclopropylboronicacid (2.39 g, 27.78 mmol), cesium fluoride (7.84 g, 51.0 mmol) andPdCl₂dppf ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),0.756 g, 0.926 mmol) were added. The mixture was degassed again withnitrogen and heated to 100° C. under nitrogen for 2 hours. The mixturewas cooled to room temperature and ethyl acetate (50 mL) was added. Themixture was stirred for 5 minutes, filtered over a pad of silica gel,washed with ethyl acetate/heptane (1:1), concentrated and purified viaflash chromatography (0 to 20% methyl tert-butyl ether in heptane) toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.18 (s,1H), 8.26 (d, J=2.7 Hz, 1H), 7.67 (d, J=2.7 Hz, 1H), 3.94 (s, 3H), 1.95(tt, J=8.4, 5.0 Hz, 1H), 0.99-0.90 (m, 2H), 0.70-0.63 (m, 2H); MS (ESI+)m/z 178 (M+H)⁺.

Example 217B (5-cyclopropyl-2-methoxypyridin-3-yl)methanol

To Example 217A (2 g, 11.29 mmol) in ethanol (10 mL) cooling in an icebath, sodium borohydride (0.470 g, 12.42 mmol) was added in portions.The mixture was stirred in an ice bath for 30 minutes. Saturated aqueousNH₄Cl (2 mL) was added, the solvent was removed, and the residue waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The water layer was extracted with ethyl acetate (10 mL×3)and the organic extracts were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give the title compound which wasused in next step. MS (APCI+) m/z 180.2 (M+1)⁺.

Example 217C 3-(bromomethyl)-5-cyclopropyl-2-methoxypyridine

To triphenylphosphine (4.83 g, 18.41 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (3.28 g,18.41 mmol) portionwise. The mixture was stirred for 30 minutesmaintaining an internal temperature<10° C., and Example 217B indichloromethane (2 mL) was added slowly at <10° C. The mixture stirredin an ice bath for 1 hour. Saturated aqueous NH₄Cl (2 mL) was added andthe organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated. Purification via chromatography on a 40 gsilica gel cartridge, eluting with ethyl acetate in heptane at a 0-30%gradient gave the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm7.96 (dd, J=4.7, 2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 4.59 (s, 1H), 4.48(s, 1H), 3.99 (s, 3H), 1.89-1.78 (m, 1H), 0.96 (ddd, J=7.0, 4.6, 1.0 Hz,2H), 0.67-0.60 (m, 2H); MS (APCI+) m/z 242.2 (M+H)⁺.

Example 217D(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopropyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 188B) (60 mg, 0.144 mmol) and3-(bromomethyl)-5-cyclopropyl-2-methoxypyridine (52.2 mg, 0.216 mmol) inN,N-dimethylformamide (2 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (24.19 mg, 0.216 mmol), (0.25 mL, 1.0 M indichloromethane) was added dropwise. The mixture was stirred in an icebath for 20 minutes, and was stirred at room temperature for 30 minutes.Dichloromethane (20 mL) and saturated aqueous NH₄Cl (5 mL) were added.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography, eluting withethyl acetate in heptane, at 0-50% gradient to yield the intermediate(2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclopropyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate,which was dissolved in methanol (2 mL) and 6M aqueous LiOH (0.5 mL). Themixture was stirred at 45° C. for 4 hours, and the pH was adjusted to1˜2 by adding 2M aqueous HCl. The mixture was filtered and purified viareverse-phase preparative HPLC with trifluoroacetic acid method to yieldthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03 (dd, J=6.5, 2.9Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.10 (s, 3H), 6.66 (d, J=2.4 Hz, 1H),5.53 (s, 1H), 4.63 (s, 1H), 4.21 (d, J=5.9 Hz, 1H), 4.16 (dd, J=13.4,0.9 Hz, 1H), 3.83-3.73 (m, 5H), 2.45 (s, 3H), 2.32 (s, 3H), 1.79-1.14(m, 7H), 1.00 (d, J=0.7 Hz, 9H), 0.92-0.79 (m, 2H), 0.56-0.41 (m, 2H);); MS (ESI+) m/z 551.2 (M+H)⁺.

Example 218(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylicacid Example 218A (E)-ethyl2-(((5,6,7,8-tetrahydronaphthalen-1-yl)methylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (1.089 g, 7.80 mmol) and magnesiumsulfate (1.503 g, 12.48 mmol) were suspended in dichloromethane (10.40mL) and the suspension was treated with triethylamine (1.087 mL, 7.80mmol). After stirring for 1 hour,5,6,7,8-tetrahydronaphthalene-1-carbaldehyde (1.0 g, 6.24 mmol) wasadded and stirring was continued for 20 hours at room temperature. Thesolid material was removed via filtration and the filtrate was washedwith water (quick wash twice) and brine, then dried over sodium sulfate,filtered, and concentrated to provide the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.60 (d, J=1.4 Hz, 1H), 7.57 (dd, J=6.5, 2.7 Hz,1H), 7.17-7.06 (m, 2H), 4.38 (d, J=1.3 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H),2.90 (t, J=6.3 Hz, 2H), 2.72 (t, J=6.1 Hz, 2H), 1.79-1.61 (m, 4H),1.23-1.11 (m, 3H); MS (ESI⁺⁾ m/z 246.2 (M+H)⁺.

Example 218B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-nitro-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.061 g, 0.081 mmol) and copper (I) triflate dimer, benzene complex(0.016 g, 0.031 mmol) were dissolved in tetrahydrofuran (15.99 mL) thathad been sparged with a N₂ stream for 4 hours. The resulting solutionwas stirred for 1.5 hours at room temperature, and Example 218A intetrahydrofuran (1 mL) was added after cooling to <5° C. in an ice waterbath. Potassium 2-methylpropan-2-olate (0.062 mL, 0.062 mmol) was addeddropwise, followed by addition of (E)-3,3-dimethyl-1-nitrobut-1-ene(0.806 g, 6.24 mmol) neat over 25 minutes, maintaining an internaltemperature<10° C. After the addition was complete, the mixture wasstirred for 15 minutes at the same temperature. The reaction mixture wasdiluted with methyl tert-butyl ether (30 mL) and stirred with 30 mL ofsaturated aqueous ammonium chloride at room temperature for 15 minutes.The organic layer was separated and washed with saturated aqueous sodiumbicarbonate and brine, then dried over sodium sulfate. After filtration,the solution was concentrated and the residue was purified by flashchromatography (0 to 30% ethyl acetate in heptane) to provide the titlecompound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 7.17-7.08 (m, 2H), 7.06(dd, J=6.8, 2.1 Hz, 1H), 5.17 (dd, J=6.1, 2.6 Hz, 1H), 4.54 (dd, J=11.0,6.0 Hz, 1H), 4.35 (qd, J=7.1, 1.1 Hz, 2H), 3.79 (t, J=7.8 Hz, 1H), 3.28(t, J=10.3 Hz, 1H), 3.06 (dd, J=7.4, 2.6 Hz, 1H), 2.89-2.81 (m, 1H),2.84-2.73 (m, 2H), 2.75-2.65 (m, 1H), 2.03-1.91 (m, 1H), 1.89-1.76 (m,2H), 1.63 (s, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.08 (s, 9H); MS (ESI⁺⁾m/z375.2 (M+H)⁺.

Example 218C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylicacid

The title compound was synthesized according to the procedure describedin Example 144A to Example 144F, substituting Example 218B for Core 10,and substituting (S)-tetrahydro-2H-pyran-2-carbonyl chloride for of(S)-tetrahydrofuran-2-carbonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.87 (d, J=7.6 Hz, 1H), 7.76 (dd, J=2.4, 0.8 Hz, 1H), 6.98 (t, J=7.6 Hz,1H), 6.95-6.84 (m, 2H), 5.52 (s, 1H), 4.61 (s, 1H), 4.21 (d, J=5.8 Hz,1H), 4.17 (dt, J=13.3, 0.8 Hz, 1H), 3.80 (dt, J=13.4, 0.9 Hz, 1H), 3.75(s, 3H), 3.38-3.24 (m, 2H), 2.75-2.64 (m, 4H), 2.57 (dt, J=16.5, 6.4 Hz,2H), 2.25-2.22 (m, 1H), 2.00-1.60 (m, 10H), 1.50 (d, J=11.8 Hz, 2H),1.43-1.22 (m, 4H), 0.99 (s, 9H); MS (ESI+) m/z 605 (M+H)⁺.

Example 219(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylicacid

The title compound was synthesized according to the procedure describedin Example 144A to Example 144F, substituting Example 218B for Core 10,substituting Intermediate 8 for Intermediate 4, and substituting(S)-tetrahydro-2H-pyran-2-carbonyl chloride for(S)-tetrahydrofuran-2-carbonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.27 (d, J=2.1 Hz, 1H), 7.90-7.80 (m, 1H), 7.19 (d, J=2.4 Hz, 1H),6.97-6.82 (m, 2H), 5.57 (d, J=21.5 Hz, 1H), 4.62 (s, 1H), 4.31-4.24 (m,2H), 3.87 (s, 3H), 3.83 (d, J=14.0 Hz, 1H), 3.76 (d, J=11.4 Hz, 1H),3.37 (s, 2H), 2.87 (s, 1H), 2.73-2.55 (m, 5H), 1.80-1.63 (m, 4H), 1.51(d, J=11.9 Hz, 2H), 1.38-1.12 (m, 4H), 1.01 (s, 9H); MS (ESI+) m/z 619(M+H)⁺.

Example 220(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-7-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 220A (2-methoxy-7-methylquinolin-3-yl)methanol

To 2-methoxy-7-methylquinoline-3-carbaldehyde [CAS#842972-37-6] (1.0 g,4.97 mmol) in ethanol (10 mL) cooling in an ice bath, sodium borohydride(0.207 g, 5.47 mmol) was added in portions. The mixture was stirred inan ice bath for 30 minutes. Saturated aqueous NH₄Cl (2 mL) was added,the solvent was removed under vacuum, and the residue was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated to provide the title compound which was usedin the next step. MS (APCI+) m/z 204.4 (M+H)⁺.

Example 220B 3-(bromomethyl)-2-methoxy-7-methylquinoline

To triphenylphosphine (2.25 g, 8.56 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (1.52 mg,8.56 mmol) portionwise. The mixture was stirred for 30 minutes,maintaining an internal temperature<10° C. Example 220A (870 mg, 4.28mmol) in dichloromethane (2 mL) was added slowly at <10° C. The mixturewas stirred at room temperature for 1 hour. Saturated aqueous NH₄Cl (2mL) was added, and the residue was partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate. The organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated.Purification via chromatography on a 40 g silica gel cartridge, elutingwith ethyl acetate in heptane at a 0-50% gradient provided the titlecompound. MS (APCI+) m/z m/z 266 (M+H)⁺.

Example 220C(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-7-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according the procedure described inExample 188C, substituting Example 220B for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.08 (dd, J=7.0, 2.5 Hz, 1H), 7.47 (dq, J=1.6, 0.8Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.20 (s, 1H), 7.18 (dd, J=8.2, 1.8 Hz,1H), 7.16-7.05 (m, 3H), 5.60 (s, 1H), 4.66 (s, 1H), 4.34-4.25 (m, 2H),3.94 (dd, J=13.8, 1.3 Hz, 1H), 3.89 (s, 3H), 3.77 (d, J=11.4 Hz, 1H),2.86 (s, 3H), 2.51 (m, 1H), 2.43 (d, J=0.8 Hz, 3H), 2.31 (s, 3H),1.75-1.16 (m, 6H), 1.02 (s, 9H); MS (ESI+) m/z 575 (M+H)⁺.

Example 221(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 221A 6-(tert-butyl)-2-methoxynicotinaldehyde

A 500 mL flask was charged with palladium acetate (0.511 g, 2.277 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (1.933 g, 4.55mmol), and cesium carbonate (37.1 g, 114 mmol). After purging the flaskwith N₂, toluene (75 mL) was added, and the mixture was heated in apreheated heating block to 80° C. After 5 minutes, the flask was cooledto room temperature, and 6-(tert-butyl)-2-chloronicotinaldehyde (15 g,76 mmol) was added as a solution in methanol (75 mL). The mixture washeated at 67° C. for 2 hours, and cooled to room temperature. Thereaction was quenched by the addition of saturated aqueous ammoniumchloride solution, the mixture was partitioned between water and methyltert-butyl ether, and the organic phase was washed with brine and driedover sodium sulfate. After filtration, the mixture was concentrated invacuo, and the residue was purified by silica gel chromatography,eluting with 0 to 10% ethyl acetate/heptanes, to afford the titlecompound. ¹H NMR (501 MHz, CDCl₃) δ ppm 10.35 (s, 1H), 8.06 (d, J=7.8Hz, 1H), 7.06-6.99 (m, 1H), 4.09 (s, 3H), 1.38 (s, 9H); MS (ESI⁺) m/z194.1 (M+H)⁺.

Example 221B (6-(tert-butyl)-2-methoxypyridin-3-yl)methanol

The title compound was prepared according to the method described forthe preparation of Intermediate 3A, substituting Example 221A for2-methoxyquinoline-3-carbaldehyde. ¹H NMR (501 MHz, Chloroform-d) δ ppm7.48 (dd, J=7.5, 0.7 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 4.64 (d, J=6.4 Hz,2H), 4.02 (s, 3H), 2.31 (t, J=6.5 Hz, 1H), 1.35 (s, 9H); MS (ESI⁺) 196.1(M+H)⁺.

Example 221C 3-(bromomethyl)-6-(tert-butyl)-2-methoxypyridine

The title compound was prepared according to the method described forthe preparation of Intermediate 3B, substituting Example 221B forIntermediate 3A. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.52 (d, J=7.6 Hz,1H), 6.86 (d, J=7.6 Hz, 1H), 4.51 (s, 2H), 4.02 (s, 3H), 1.34 (s, 9H);MS (ESI⁺⁾m/z 258.1 (M+H)⁺.

Example 221D (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure described forExample 129H, substituting Example 129C for Example 129G. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.41 (d, J=6.8 Hz, 1H), 7.14-7.01 (m, 3H), 4.20-4.02(m, 4H), 3.94 (m, 1H), 3.45 (m, 1H), 2.95 (m, 1H), 2.23 (s, 3H), 2.07(m, 1H), 1.19 (t, J=7.1 Hz, 3H), 0.91 (s, 9H); MS (ESI⁺) m/z 306.2(M+H)⁺.

Example 221E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the method described forExample 98A, substituting Example 221D for Example 96E and substituting(S)-tetrahydro-2H-pyran-2-carboxylic acid for(S)-tetrahydrofuran-2-carboxylic acid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.94 (m, 1H), 7.11 (m, 3H), 5.45 (m, 1H), 4.41 (m, 2H), 4.15 (q, J=7.1Hz, 2H), 3.95-3.64 (m, 2H), 3.32 (m, 1H), 2.98 (m, 1H), 2.32 (s, 3H),2.21 (t, J=3.8 Hz, 1H), 1.76-1.06 (m, 6H), 1.24 (t, J=7.1 Hz, 3H), 0.98(s, 9H); MS (ESI⁺) m/z 418.3 (M+H)⁺.

Example 221F (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((6-(tert-butyl)-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure of Example129G, substituting Example 221E for Example 129C and substitutingExample 221C for Example 129F. The crude title compound thus obtainedwas used directly without further purification. MS (APCI⁺) m/z 595.5(M+H)⁺.

Example 221G(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure of Example98B, substituting Example 221F for Example 98A. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.99 (m, 1H), 7.11 (m, 3H), 6.83 (d, J=7.6 Hz, 1H), 6.67(d, J=7.7 Hz, 1H), 5.54 (m, 1H), 4.57 (m, 1H), 4.16 (d, J=5.6 Hz, 1H),4.07 (d, J=13.1 Hz, 1H), 3.84-3.71 (m, 4H), 3.75 (s, 3H), 2.35 (m, 1H),2.29 (m, 2H), 2.27 (s, 3H), 1.66-1.17 (m, 4H), 1.23 (s, 9H), 0.96 (s,9H); MS (ESI⁺) m/z 567.2 (M+H)⁺.

Example 222(2S,3R,4S,5S)-3-tert-butyl-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)pyrrolidine-2-carboxylicacid Example 222A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure described inExample 170B, substituting 3,4-dihydro-2H-pyran-6-carbonyl chloride for(S)-tetrahydro-2H-pyran-2-carbonyl chloride. MS (ESI+) m/z 416 (M+H)⁺.

Example 222B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 222A, 60 mg, 0.144 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (60 mg, 0.222mmol) were dissolved in dry N,N-dimethylformamide (1 mL). After coolingin an ice bath, potassium 2-methylpropan-2-olate (0.217 mL, 0.217 mmol)1 M solution in tetrahydrofuran was added dropwise over 15 minutes.After 30 minutes, the reaction was acidified with 1M aqueous HCl (5drops mL) and warmed to ambient temperature. The mixture was dilutedwith 1 mL of water and the organics were taken up in 1 mL ofdichloromethane. The crude material was purified using a 10 g silica gelcolumn and was eluted with 5-50% ethyl acetate/heptanes over 40 minutesto provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (s,1H), 7.91 (dd, J=7.1, 2.0 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.99 (dqd,J=12.2, 7.1, 2.3 Hz, 3H), 5.46 (d, J=5.7 Hz, 1H), 5.25 (d, J=4.2 Hz,1H), 4.62 (d, J=1.6 Hz, 1H), 4.31-4.22 (m, 2H), 4.15-4.02 (m, 2H), 3.86(s, 3H), 3.81 (d, J=13.9 Hz, 1H), 3.73 (s, 1H), 3.50 (s, 1H), 2.39 (d,J=1.6 Hz, 1H), 2.32 (s, 3H), 1.97-1.75 (m, 2H), 1.58 (s, 1H), 1.18-1.10(m, 3H), 1.03 (s, 9H), 0.90-0.80 (m, 1H); MS (APCI+) m/z 605 (M+H)⁺.

Example 222C(2S,3R,4S,5S)-3-tert-butyl-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)pyrrolidine-2-carboxylicacid

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(o-tolyl)pyrrolidine-2-carboxylatefrom Example 222B (74 mg, 0.122 mmol) and lithium hydroxide (29.3 mg,1.224 mmol) were dissolved in methanol (1 mL) and water (0.5 mL) andtetrahydrofuran (0.5 mL). The reaction mixture was warmed at 45° C. for16 hours. The solvent was removed and the reaction was acidified with 2M aqueous HCl (0.612 mL). The crude material was purified using a 12 gsilica gel column and was eluted with an ethyl acetate/heptanes/ethanolsolvent system to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.30-8.22 (m, 1H), 7.99 (dd, J=6.5, 2.4 Hz, 1H), 7.20 (d, J=2.4Hz, 1H), 7.00 (dtt, J=10.5, 7.3, 3.7 Hz, 3H), 5.47 (d, J=5.8 Hz, 1H),5.22 (s, 1H), 4.60 (d, J=1.9 Hz, 1H), 4.32-4.25 (m, 2H), 3.87 (s, 4H),3.71 (d, J=9.4 Hz, 1H), 3.50 (s, 1H), 2.31 (s, 3H), 1.96-1.85 (m, 1H),1.82 (s, 1H), 1.57 (s, 1H), 1.40 (s, 1H), 1.03 (s, 9H), 0.91-0.82 (m,1H); MS (APCI+) m/z 577 (M+H)⁺.

Example 223(2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 170C, substituting 3-(bromomethyl)-5-chloro-2-methoxypyridinefor 3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 8.06-7.99 (m, 1H), 7.91 (dt, J=2.6, 0.7 Hz, 1H),7.11 (s, 3H), 6.84 (dt, J=2.8, 1.0 Hz, 1H), 5.55 (s, 1H), 4.65 (s, 1H),4.28-4.16 (m, 2H), 3.97 (s, 1H), 3.85-3.71 (m, 5H), 3.36 (s, 2H), 2.32(s, 3H), 1.75-1.25 (m, 6H), 1.02 (s, 9H); MS (ESI+) m/z 545 (M+H)⁺.

Example 224(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethoxy)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 170C, substituting2-(bromomethyl)-1-methoxy-4-(trifluoromethoxy)benzene for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 8.07-7.96 (m, 1H), 7.15-6.99 (m, 4H), 6.89 (d,J=8.9 Hz, 1H), 6.55-6.51 (m, 1H), 5.54 (s, 1H), 4.63 (s, 1H), 4.27-4.19(m, 2H), 3.85 (dt, J=13.5, 0.8 Hz, 1H), 3.77 (d, J=11.3 Hz, 1H), 3.69(s, 3H), 3.37 (s, 2H), 2.46 (s, 1H), 2.32 (s, 3H), 1.72-1.26 (m, 6H),1.00 (s, 9H); MS (ESI+) m/z 594 (M+H)⁺.

Example 225(2S,3R,4S,5S)—N-(6-aminopyridine-2-sulfonyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxamide

(2S,3R,4S,5S)-3-(tert-Butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-cyclopropylphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid (Example 171B) (48.8 mg, 0.083 mmol) anddi(1H-imidazol-1-yl)methanone (20.09 mg, 0.124 mmol) were combined inN,N-dimethylformamide (1 mL) and warmed to 65° C. for 1 hour.6-Aminopyridine-2-sulfonamide (14.31 mg, 0.083 mmol) was dissolved in0.3 mL of N,N-dimethylformamide and sodium hydride (3.47 mg, 0.087 mmol)(60% dispersion in mineral oil) was added in portions. The reaction wasstirred at ambient temperature for one hour, the mixture was added tothe NaH/sulfonamide suspension and the resulting mixture was stirred atambient temperature for 16 hours. The solvent was reduced in volume andthe crude material was quenched with water and 1N aqueous HCl was addeddropwise to acidic pH. The resulting precipitate was filtered and washedwith water. The crude precipitate was purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound as the trifluoroacetic acid salt. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.74 (d, J=2.5 Hz, 1H), 7.63 (dd, J=7.5, 1.7 Hz, 1H),7.44 (dd, J=8.3, 7.3 Hz, 1H), 7.13 (dd, J=7.3, 0.9 Hz, 1H), 7.11-7.04(m, 2H), 6.94 (dd, J=7.5, 1.6 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 6.64 (dd,J=8.4, 0.8 Hz, 1H), 5.89 (d, J=6.1 Hz, 1H), 4.57 (d, J=2.6 Hz, 1H), 4.31(dd, J=6.1, 1.7 Hz, 1H), 4.23 (d, J=13.4 Hz, 1H), 3.95 (d, J=9.0 Hz,1H), 3.91 (s, 1H), 3.77 (s, 1H), 3.74 (s, 3H), 3.69-3.56 (m, 1H),3.33-3.27 (m, 3H), 2.55 (t, J=2.2 Hz, 1H), 2.27-2.13 (m, 2H), 2.04-1.79(m, 4H), 1.71-1.62 (m, 1H), 1.54-1.43 (m, 1H), 1.36 (dt, J=8.8, 4.3 Hz,2H), 1.22-1.07 (m, 1H), 1.00 (s, 9H), 0.96-0.82 (m, 2H), 0.71 (ddd,J=9.1, 5.5, 3.8 Hz, 1H), 0.46 (ddd, J=9.5, 6.4, 3.7 Hz, 1H); MS (APCI+)m/z 746 (M+H)⁺.

Example 226(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-3-methoxypyridin-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 226A (6-bromo-3-methoxypyridin-2-yl)methanol

6-Bromo-3-methoxypicolinaldehyde (0.880 g, 4.07 mmol) was suspended inCH₃OH (20 mL) and the mixture was cooled to 0° C. Sodium borohydride(0.154 g, 4.07 mmol) was added, causing bubbling. The reaction mixturewas stirred at 0° C. for 15 minutes, and the flask was removed from theice bath and was allowed to stir at room temperature for 2 hours. Thereaction mixture was then concentrated in vacuo, and the crude materialwas taken up in methyl tert-butyl ether and saturated aqueous NaHCO₃solution. The phases were separated, and the organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo to provide the titlecompound. ¹H NMR (501 MHz, CDCl₃) δ ppm 8.15 (d, J=2.4 Hz, 1H), 7.75 (m1H), 4.66 (dt, J=6.3, 0.7 Hz, 2H), 2.16 (t, J=6.3 Hz, 1H); MS (ESI⁺⁾m/z218.0 (M+H)⁺.

Example 226B6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxypyridine

(6-Bromo-3-methoxypyridin-2-yl)methanol (0.718 g, 3.29 mmol),tert-butyldimethylsilyl chloride (0.596 g, 3.95 mmol), and imidazole(0.336 g, 4.94 mmol) were stirred in CH₂Cl₂ (13 mL) overnight at roomtemperature. The reaction was then quenched with 3 mL of CH₃OH, and thereaction mixture was stirred at room temperature for 10 minutes. Themixture was diluted with CH₂Cl₂ and washed twice with saturated aqueousNaHCO₃ solution and once with brine. The organic solution was dried overNa₂SO₄, filtered and concentrated in vacuo to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.34 (d, J=8.5 Hz, 1H), 7.05 (d,J=8.5 Hz, 1H), 4.80 (s, 2H), 3.84 (s, 3H), 0.92 (s, 9H), 0.12 (s, 6H).

Example 226C6-(tert-butyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxypyridine

To a 100 mL 2-neck round bottom flask was added nickelchloride-dimethoxyethane adduct (0.066 g, 0.300 mmol) and1,3-dicyclohexyl-1H-imidazol-3-ium tetrafluoroborate (0.096 g, 0.300mmol), followed by a solution of6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxypyridine(0.997 g, 3.00 mmol) in tetrahydrofuran (12 mL). The system wasevacuated and back-filled with nitrogen seven times, then the reactionwas cooled to −10° C., and tert-butylmagnesium chloride (1M intetrahydrofuran) (6.00 mL, 6.00 mmol) was added dropwise. The reactionmixture was stirred at −10° C. for 150 minutes. The reaction was thenquenched with chips of ice and allowed to warm to room temperature. Themixture was poured into saturated aqueous NH₄Cl solution and wasextracted three times with ethyl acetate. The combined organic extractswere washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Silica gel chromatography, eluting with 0 to 40% ethylacetate-heptanes, afforded the crude title compound. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.18 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.86 (s,2H), 3.82 (s, 3H), 1.35 (s, 9H), 0.92 (s, 9H), 0.10 (s, 6H); MS (ESI⁺)m/z 310.1 (M+H)⁺.

Example 226D (6-(tert-butyl)-3-methoxypyridin-2-yl)methanol

6-(tert-Butyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxypyridine(0.356 g, 1.150 mmol) in tetrahydrofuran (11 mL) was treated withtetrabutylammonium fluoride trihydrate (1.814 g, 5.75 mmol), and thereaction was stirred overnight at room temperature. The reaction mixturewas poured into a mixture of saturated aqueous NH₄Cl and brine solutionin a separatory funnel, and the mixture was extracted three times withethyl acetate. The combined extracts were dried over Na₂SO₄, filtered,and concentrated in vacuo to provide the title compound, which was takendirectly into the next step without further purification. MS (APCI⁺) m/z196.3 (M+H)⁺.

Example 226E 2-(bromomethyl)-6-(tert-butyl)-3-methoxypyridine

(6-(tert-Butyl)-3-methoxypyridin-2-yl)methanol (970 mg, 4.97 mmol) andtriphenylphosphine (1.99 g, 7.59 mmol) were dissolved in dichloromethane(25 mL) and cooled in an ice bath. N-Bromosuccinimide (1.31 g, 7.36mmol) was added in portions, keeping the internal temperature below 10°C. The ice bath was removed, and after stirring for 15 minutes, thereaction was complete. The reaction was quenched by adding 25 mL ofwater, and was stirred for 5 minutes. The layers were separated, and theorganics were washed twice with water and filtered through a frittedcartridge layered with a pad of silica (1 cm), eluting with heptanes.The filtrates were concentrated. The crude residue was taken up in pureheptanes and filtered through a fritted cartridge layered with a pad ofsilica (3 cm), eluting with heptanes to give the title compound. ¹H NMR(501 MHz, DMSO-d₆) δ ppm 7.40 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H),4.60 (s, 2H), 3.86 (s, 3H), 1.28 (s, 9H); MS (ESI⁺) m/z 258 & 260(M+H)⁺.

Example 226F ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((6-(tert-butyl)-3-methoxypyridin-2-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

Example 170B (98.7 mg, 0.236 mmol), after being azeotroped with toluene(3×2 mL), and Example 226E (91.4 mg, 0.354 mmol) were dissolved in dryN,N-dimethylformamide (1 mL). After cooling in an ice bath, a potassium2-methylpropan-2-olate (300 μL, 0.300 mmol) solution was added dropwiseover 2 minutes. The reaction was diluted with methanol (1 mL), filteredand purified by reverse phase chromatography (trifluoroacetic acidmethod) to give the title compound as the trifluoroacetic acid salt. ¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.95-7.88 (m, 1H), 7.22 (d, J=8.5Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.13-7.01 (m, 3H), 5.41 (s, 1H), 4.56(s, 1H), 4.30 (dd, J=5.8, 1.1 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.95 (d,J=11.4 Hz, 1H), 3.90 (d, J=11.3 Hz, 1H), 3.76-3.67 (m, 1H), 3.54 (s,3H), 2.93 (s, 2H), 2.31 (d, J=2.1 Hz, 1H), 2.21 (s, 3H), 1.63 (d, J=12.9Hz, 1H), 1.55-1.27 (m, 5H), 1.25 (s, 9H), 1.19 (t, J=7.1 Hz, 3H), 0.89(s, 9H). MS (ESI⁺) m/z 595 (M+H)⁺.

Example 226G(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-3-methoxypyridin-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 226F (106.8 mg, 0.150 mmol) and lithium hydroxide (1M aqueous)(1.0 mL, 1.0 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) wasstirred at 50° C. for 16 hours. The reaction mixture was acidified with1.2 mL 1N aqueous HCl, and concentrated in vacuo. The residue waspurified by reverse phase using the trifluoroacetic acid method toprovide the title compound as the trifluoroacetic acid salt. ¹H NMR (400MHz, DMSO-d₆, 120° C.) δ ppm 7.97 (dd, J=5.6, 3.7 Hz, 1H), 7.24 (d,J=8.6 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.13-7.00 (m, 3H), 5.41 (s, 1H),4.54 (d, J=2.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 1H), 3.94 (q, J=11.6 Hz, 2H),3.74 (d, J=11.8 Hz, 1H), 3.56 (s, 3H), 3.37 (s, 1H), 2.89 (s, 1H), 2.36(d, J=1.7 Hz, 1H), 2.18 (s, 3H), 1.69-1.58 (m, 1H), 1.57-1.29 (m, 5H),1.27 (s, 9H), 0.89 (s, 9H); MS (ESI+) m/z 567 (M+H)⁺.

Example 227(2S,3R,4S,5S)-3-tert-butyl-4-({[2-methoxy-5-(trifluoromethyl)pyridin-3-yl](²H₂)methyl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 227A methyl 2-methoxy-5-(trifluoromethyl)nicotinate

Methanol (12.5 mL) was added to3-bromo-2-methoxy-5-(trifluoromethyl)pyridine [CAS#124432-63-9] (5 g,19.53 mmol) and triethylamine (4.25 mL, 30.5 mmol) in a 50 mL Hast Creactor, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (0.143 g, 0.195 mmol) was added. The mixture was purgedwith argon and pressurized with CO. Agitation was set for 1200 RPM andthe mixture was stirred under 60 psi of carbon monoxide at 100° C. for10 hours. The mixture was allowed to cool to room temperature. Thereaction solution was concentrated and filtered via a short silica gelcolumn eluting with ethyl acetate. The filtrate was concentrated toprovide the title compound, which used in next step without furtherpurification. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.60 (td, J=1.9, 0.9Hz, 1H), 8.46-8.29 (m, 1H), 4.13 (s, 3H), 3.96 (s, 3H); MS (ESI+) m/z236 (M+H)⁺.

Example 227B (2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol-d₂

To methyl 2-methoxy-5-(trifluoromethyl)nicotinate (1.23 g, 5.23 mmol) inmethanol-d₄ (2 mL) and tetrahydrofuran (6 mL) was added sodiumborodeuteride (0.263 g, 6.28 mmol) portionwise. The mixture was stirredat room temperature for 30 minutes, at which point another 0.2equivalent of NaBD₄ was added and stirring was continued for another 30minutes. Saturated aqueous NH₄Cl (2 mL) and ethyl acetate (30 mL) wereadded. The mixture was washed with brine, dried over sodium sulfate,filtered, and concentrated. Purification via chromatography on a 40 gsilica gel cartridge, eluting with ethyl acetate in heptane at 0-30%gradient provided the title compound. ¹H NMR (400 MHz, Chloroform-d) δppm 8.38 (dq, J=2.3, 1.2 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 4.05 (s, 3H);MS (ESI+) m/z 210 (M+H)⁺.

Example 227C 3-(bromomethy-d₂)-2-methoxy-5-(trifluoromethyl)pyridine

To triphenylphosphine (2031 mg, 7.75 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (1379 mg,7.75 mmol) portionwise. The mixture was stirred for 30 minutesmaintaining an internal temperature<10° C.(2-Methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol-d₂ (810 mg, 3.87mmol) in dichloromethane (2 mL) was added slowly at <10° C. The mixturewas stirred at room temperature for 1 hour. Saturated aqueous NH₄Cl (2mL) was added and the solvent was removed. The residue was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated. Purification via chromatography on a 40 gsilica gel cartridge, eluting with ethyl acetate in heptane at 0-30%gradient provided the title compound. MS (APCI+) m/z 274 (M+H)⁺.

Example 227D(2S,3R,4S,5S)-3-tert-butyl-4-({[2-methoxy-5-(trifluoromethyl)pyridin-3-yl](²H₂)methyl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 188B, 70 mg, 0.168 mmol) and Example 227C (68.4 mg, 0.251 mmol)in N,N-dimethylformamide (2 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (28.2 mg, 0.251 mmol) (0.25 mL, 1.0 M intetrahydrofuran) was added dropwise. The mixture was stirred in the icebath for 20 minutes, and stirred at room temperature for 30 minutes.Dichloromethane (20 mL) and saturated aqueous NH₄Cl (5 mL) were added.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography, eluting withethyl acetate/methanol (9:1) in heptane, at 0-30% gradient to yield theintermediate ester which was dissolved in methanol (2 mL) and 6 Naqueous LiOH (0.5 mL). The mixture was stirred at 45° C. for 4 hours.The pH was adjusted to 1˜2 by adding 2N aqueous HCl. Dichloromethane (10mL) was added and the organics were washed with brine, dried over MgSO₄,filtered, and concentrated. Purification via chromatography on a 12 gsilica gel cartridge, eluting with ethyl acetate/methanol (9:1) inheptane at 0-50% gradient provided the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.28 (dt, J=2.4, 1.2 Hz, 1H), 8.06-7.98 (m, 1H), 7.18 (d,J=2.6 Hz, 1H), 7.06 (t, J=6.6 Hz, 3H), 5.55 (s, 1H), 4.64 (d, J=1.9 Hz,1H), 4.27 (d, J=5.9 Hz, 1H), 3.87 (s, 3H), 3.76 (d, J=11.4 Hz, 1H), 3.38(s, 2H), 2.64 (m, 1H), 2.32 (s, 3H), 1.75-1.24 (m, 6H), 1.02 (s, 9H); MS(ESI+) m/z 581 (M+H)⁺.

Example 228(2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)pyridin-3-yl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 228A 3-bromo-2-methoxy-d₃-5-(trifluoromethyl)pyridine

To the mixture of 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (5.0 g,19.20 mmol) and methanol-d₃ (1.165 mL, 28.8 mmol) inN,N-dimethylformamide (10 mL) was added sodium hydride (1.152 g, 28.8mmol) portionwise. The reaction was stirred at room temperature for 1hour. Ethyl acetate (20 mL) and saturated aqueous NH₄Cl (2 mL) wereadded. The organics were washed with brine, dried over Na₂SO₄, filtered,and concentrated to provide the title compound. MS (APCI+) m/z 239.2(M+H)⁺.

Example 228B methyl 2-methoxy-d₃-5-(trifluoromethyl)nicotinate

To Example 228A (3.9 g, 15.06 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Heraeus)(121 mg, 0.166 mmol) in a 100 mL Hast C reactor were add methanol (50mL) and triethylamine (4.2 mL, 30.1 mmol). The reactor was degassed withnitrogen several times. Carbon monoxide was added and the reaction washeated to 100° C. for 2.18 hours at 60 psi±8 psi of carbon monoxide, andat 100° C. for 10 hours. The mixture was allowed to cool to roomtemperature and was filtered via a short silica gel column eluting withethyl acetate. The filtrate was concentrated to provide the titlecompound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.60 (q, J=1.1 Hz, 1H),8.46-8.30 (m, 1H), 3.96 (s, 3H), 0.10 (d, J=2.7 Hz, 1H); MS (ESI+) m/z239 (M+H)⁺.

Example 228C (2-methoxy-d₃-5-(trifluoromethyl)pyridin-3-yl)methanol-d₂

To methyl 2-methoxy-d₃-5-(trifluoromethyl)nicotinate (1.7 g, 7.14 mmol)in tetrahydrofuran (8 mL) and methanol-d₄ (2 mL) was added sodiumborodeuteride (0.359 g, 8.57 mmol) in portions at ambient temperature.The mixture was stirred for 2 hours. Saturated aqueous NH₄Cl (2 mL) andethyl acetate (50 mL) were added. The organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated.Purification via chromatography on a 40 g silica gel cartridge, elutingwith ethyl acetate in heptane at 0-30% gradient, provided the titlecompound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 8.40 (p, J=1.1 Hz, 1H),7.88 (d, J=2.4 Hz, 1H); MS (ESI+) m/z 213 (M+H)⁺.

Example 228D 3-(bromomethyl-d₂)-2-methoxy-d₃-5-(trifluoromethyl)pyridine

To triphenylphosphine (2.72 g, 10.37 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (1.845 g,10.37 mmol) portionwise. The mixture was stirred for 30 minutesmaintaining an internal temperature<10° C., and Example 228C (1.1 g,5.18 mmol) in dichloromethane (2 mL) was added slowly at <10° C. Themixture was stirred at room temperature for 1 hour. Saturated aqueousNH₄Cl (2 mL) was added and the solvent was removed. The residue waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic layer was washed with brine, dried over sodiumsulfate, filtered, and concentrated. Purification via chromatography ona 40 g silica gel cartridge, eluting with ethyl acetate in heptane at0-30% gradient provided the title compound. ¹H NMR (500 MHz,Chloroform-d) δ ppm 8.43 (ddq, J=6.9, 2.1, 1.0 Hz, 1H), 7.87 (ddd,J=28.3, 2.5, 0.6 Hz, 1H).

Example 228E(2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)pyridin-3-yl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 188B, 70 mg, 0.168 mmol) and Example 228D (69.2 mg, 0.251 mmol)in N,N-dimethylformamide (2 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (28.2 mg, 0.251 mmol) (0.25 mL, 1.0 M intetrahydrofuran) was added dropwise. The mixture was stirred in ice bathfor 20 minutes, and stirred at room temperature for 30 minutes.Dichloromethane (20 mL) and saturated aqueous NH₄Cl (5 mL) were added.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography on a 12 gsilica gel cartridge, eluting with ethyl acetate/methanol (9:1) inheptane, at 0-50% gradient to yield the intermediate ester which wasdissolved in methanol (2 mL) and 6N aqueous LiOH (0.5 mL). The mixturewas stirred at 45° C. for 4 hours and the pH was adjusted to 1˜2 byadding 2M aqueous HCl. The mixture was dissolved in dichloromethane (10mL), washed with brine, dried over Na₂SO₄, filtered, and concentrated.The residue was purified via chromatography on a 12 g silica gelcartridge, eluting with ethyl acetate/methanol (9:1) in heptane at 0-50%gradient to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.27 (q, J=1.2 Hz, 1H), 8.06-7.99 (m, 1H), 7.17 (d, J=1.2 Hz, 1H), 7.05(t, J=6.6 Hz, 3H), 5.55 (s, 1H), 4.64 (s, 1H), 4.27 (d, J=5.8 Hz, 1H),3.76 (d, J=11.4 Hz, 1H), 3.38 (s, 2H), 2.64 (m, 1H), 2.32 (s, 3H),1.71-1.22 (m, 6H), 1.02 (s, 9H); MS (ESI+) m/z 584 (M+H)⁺.

Example 229(2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 229A (E)-ethyl2-((5-chloro-2-methylbenzylidene)amino)acetate

A mixture of ethyl 2-aminoacetate hydrochloride (2.4 g, 17.19 mmol) andmagnesium sulfate (4.14 g, 34.4 mmol) in dichloromethane (29 mL)(anhydrous) was treated with triethylamine (2.397 mL, 17.19 mmol),stirred for 10 minutes and treated with 5-chloro-2-methylbenzaldehyde(2.66 g, 17.19 mmol) as a solution in 1 mL dichloromethane. The flaskwas capped and stirred at ambient temperature for 16 hours. The solidmaterial was filtered, and the filtrate was washed with water. Theorganics were dried with Na₂SO₄, filtered, and concentrated to providethe title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 8.56 (t, J=1.4Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.31 (dd, J=8.2, 2.4 Hz, 1H), 7.22-7.01(m, 1H), 4.45 (d, J=1.3 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.50 (s, 3H),1.34 (t, J=7.1 Hz, 3H).

Example 229B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.220 g, 0.292 mmol) and copper(II) trifluoromethanesulfonate (0.059 g,0.117 mmol) were dissolved in tetrahydrofuran (28 mL) that had beensparged with a N₂ stream for 1 hour. The resulting solution was stirredfor 1 hour at ambient temperature (continued nitrogen sparge), and(E)-ethyl 2-((5-chloro-2-methylbenzylidene)amino)acetate from Example229A (3.5 g, 14.60 mmol) in 1 mL tetrahydrofuran was added. Theresulting solution was cooled to <5° C. in an ice water bath. Potassium2-methylpropan-2-olate, 1M in tetrahydrofuran (0.263 mL, 0.263 mmol) wasadded dropwise, followed by addition of(E)-3,3-dimethyl-1-nitrobut-1-ene (1.886 g, 14.60 mmol) in 1 mLtetrahydrofuran over 2 minutes, maintaining a temperature less than 7°C. The reaction mixture was stirred for 2 hours at 0° C. The mixture wasquenched with 30 mL of saturated aqueous ammonium chloride and 75 mL ofethyl acetate and warmed to ambient temperature. The organic layer wasseparated and washed with saturated aqueous ammonium chloride (2×30 mL)and brine and filtered through a pad of silica gel. The filtrate wasconcentrated, and the crude material was triturated with 70 mL heptane,and filtered to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 7.46 (d, J=2.3 Hz, 1H), 7.23 (dd, J=8.1, 2.3 Hz, 1H), 7.19 (d, J=8.2Hz, 1H), 5.28 (dd, J=7.1, 3.6 Hz, 1H), 4.64 (t, J=6.8 Hz, 1H), 4.22 (qq,J=6.9, 3.7 Hz, 2H), 3.74 (dd, J=7.7, 6.6 Hz, 1H), 3.66 (t, J=6.6 Hz,1H), 3.13 (dd, J=7.7, 3.6 Hz, 1H), 2.36 (s, 3H), 1.27 (t, J=7.1 Hz, 3H),0.95 (s, 9H); MS (APCI+) m/z 369 (M+H)⁺.

Example 229C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-nitropyrrolidine-2-carboxylatefrom Example 229B (2.5 g, 6.78 mmol) in toluene (8 mL) and saturatedaqueous NaHCO₃ (8 mL) was added allyl carbonochloridate (0.743 mL, 6.78mmol) dropwise at ambient temperature. The mixture was stirred atambient temperature for 16 hours. Ethyl acetate (30 mL) and water (25mL) were added and the organic layer was separated, washed with brineand concentrated. The resulting material was purified on a 24 gcartridge eluting with a gradient of 0-100% ethyl acetate/heptanes overa period of 20 minute to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.83 (s, 1H), 7.17 (dd, J=8.1, 2.3 Hz, 1H), 7.12 (d,J=8.2 Hz, 1H), 5.80 (s, 1H), 5.70-5.60 (m, 1H), 5.48 (d, J=8.6 Hz, 1H),5.15 (m, 1H), 4.92-4.63 (m, 1H), 4.54 (d, J=3.4 Hz, 1H), 4.47 (s, 2H),4.23 (qd, J=7.1, 2.4 Hz, 2H), 3.01 (t, J=3.0 Hz, 1H), 2.33 (s, 3H), 1.27(t, J=7.1 Hz, 3H), 0.98 (s, 9H); MS (APCI+) m/z 453 (M+H)⁺.

Example 229D (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

To potassium dichromate (8.77 g, 29.8 mmol) in 6N aqueous HCl (136 mL)was added zinc (9.96 g, 152 mmol) portionwise under N₂ atmosphere atambient temperature. After the almost complete dissolution of zinc(after ˜2 hours), the formed chromium(II) chloride was transferred viacannula to a refluxing solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate(Example 229C, 2.5 g, 5.52 mmol) in ethanol (115 mL) under N₂. Thereaction mixture was refluxed at 86° C. internally for 20 hours, cooled,and concentrated. The mixture was extracted with dichloromethane threetimes. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue (2.15 g) was subjected tore-esterification. Acetyl chloride (2 mL, 28.13 mmol) was added slowlyto an ice cooled flask containing ethanol (6 mL). After the addition wascomplete, the reaction was stirred at ambient temperature for 5 minutesbefore pouring the resulting HCl/ethanol solution into a separate flaskcontaining the crude ester/acid mixture. The mixture was heated to 65°C. for an additional hour. The mixture was cooled to ambienttemperature, concentrated and the residue was purified on a 40 gcartridge eluting with a gradient of 0-65% ethyl acetate/heptanes over aperiod of 20 minutes to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.83 (s, 1H), 7.20 (d, J=2.1 Hz, 2H), 5.72 (d, J=99.1 Hz,1H), 5.22 (d, J=40.3 Hz, 2H), 4.80 (d, J=89.9 Hz, 1H), 4.56 (s, 1H),4.47 (d, J=14.1 Hz, 1H), 4.36 (s, 1H), 4.19 (qd, J=7.1, 4.0 Hz, 2H),2.75 (d, J=5.4 Hz, 1H), 2.34 (s, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.01 (s,9H); MS (APCI+) m/z 422 (M+H)⁺.

Example 229E (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

(2S,3R,5S)-1-Allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-oxopyrrolidine-1,2-dicarboxylatefrom Example 229D (1.3 g, 3.08 mmol) was dissolved in ethanol (15.41mL). Sodium borohydride (0.233 g, 6.16 mmol) was added after cooling thereaction to <−10° C. in an ice acetone bath. The ice bath was removedand the mixture was allowed to warm to room temperature over about 20minutes. The mixture was concentrated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate for about 30 minutes.The organics were concentrated and purified on a 24 g silica gelcartridge, eluting with 0-60% ethyl acetate/heptanes over period of 20minutes. The enriched fractions were combined and rechromatographed on a12 g silica gel cartridge eluting with 100% dichloromethane over aperiod of 12 minutes to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.94 (s, 1H), 7.09 (d, J=1.5 Hz, 2H), 5.73 (m, 1H), 5.18(s, 1H), 4.97 (s, 1H), 4.80 (s, 1H), 4.68 (m, 1H), 4.46 (m, 1H), 4.39(s, 2H), 4.27 (s, 1H), 4.20-4.07 (m, 2H), 2.25 (s, 3H), 2.22 (s, 1H),1.24 (t, J=7.1 Hz, 3H), 0.95 (s, 9H); MS (APCI+) m/z 424 (M+H+).

Example 229F (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-1-Allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylatefrom Example 229E (200 mg, 0.472 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (175 mg, 0.684 mmol) weredissolved in dry N,N-dimethylformamide (2.4 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (0.684 mL, 0.684 mmol) 1 Msolution in tetrahydrofuran was added dropwise over 2 minutes. After 60minutes, the mixture was acidified with 1M aqueous HCl (0.17 mL) andwarmed to ambient temperature. The mixture was diluted with water (10mL), extracted with dichloromethane, and loaded onto a 12 g silica gelcolumn, eluting with 0-70% ethyl acetate/heptanes over 20 minutes toprovide the title compound. ¹H NMR (501 MHz, DMSO-d₆) δ ppm 7.94 (d,J=31.4 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.21-7.04 (m, 2H), 6.79 (d,J=2.4 Hz, 1H), 5.73 (d, J=142.7 Hz, 1H), 5.33-5.14 (m, 1H), 5.10 (s,1H), 4.99-4.60 (m, 1H), 4.51 (m, 3H), 4.37 (s, 1H), 4.27 (d, J=13.6 Hz,1H), 4.09 (dd, J=7.1, 3.6 Hz, 2H), 3.85 (d, J=13.6 Hz, 1H), 3.72 (s,3H), 2.27 (s, 3H), 2.22-2.07 (m, 2H), 2.04-1.87 (m, 3H), 1.81-1.71 (m,1H), 1.11 (t, J=7.1 Hz, 3H), 1.01 (s, 9H); MS (APCI+) m/z 599 (M+H)⁺.

Example 229G (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylatefrom Example 229F (150 mg, 0.250 mmol) in acetonitrile/water (4.29 mL,10:1) was added tetrakis(triphenylphosphine)palladium(0) (6.36 mg, 5.51μmol) and diethylamine (0.052 mL, 0.501 mmol). The mixture was stirredat ambient temperature for 16 hours. Dichloromethane and water wereadded, and the organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude material was purified bychromatography, eluting on a 12 g cartridge with a gradient of 0-70%ethyl acetate/heptanes over 20 minutes to provide the title compound. ¹HNMR (501 MHz, DMSO-d₆) δ ppm 7.80 (d, J=2.4 Hz, 1H), 7.69 (d, J=2.3 Hz,1H), 7.17 (dd, J=8.1, 2.4 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 6.87 (d,J=2.4 Hz, 1H), 4.25-4.22 (m, 1H), 4.20 (d, J=12.8 Hz, 1H), 4.15-4.06 (m,2H), 4.01 (dd, J=4.6, 1.5 Hz, 1H), 3.72 (s, 3H), 3.67 (d, J=12.9 Hz,1H), 3.60 (t, J=6.8 Hz, 1H), 3.22 (t, J=7.2 Hz, 1H), 2.34 (dd, J=6.6,1.5 Hz, 1H), 2.27 (s, 3H), 2.23-2.16 (m, 2H), 2.01-1.88 (m, 3H),1.83-1.76 (m, 1H), 1.18 (t, J=7.1 Hz, 3H), 0.95 (s, 9H); MS (APCI+) m/z515 (M+H)⁺.

Example 229H (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-2-carboxylatefrom Example 229G (116 mg, 0.225 mmol) in dichloromethane (0.6 mL) at 0°C. was added triethylamine (0.141 mL, 1.013 mmol) followed by additionof (S)-tetrahydro-2H-pyran-2-carbonyl chloride (56.9 mg, 0.383 mmol) asa solution in 1 mL dichloromethane. After stirring for 15 minutes, themixture was quenched with 5 mL of saturated aqueous sodium bicarbonate.The crude organics were chromatographed using a 12 g silica gelcartridge with a gradient of 0-65% ethyl acetate/heptanes over a periodof 20 minutes to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.06-7.90 (m, 1H), 7.12 (m, 3H), 7.04 (d, J=1.6 Hz, 1H), 6.98 (d,J=7.5 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 5.52 (s, 1H), 4.67 (s, 1H), 4.22(d, J=13.6 Hz, 1H), 4.16 (d, J=5.7 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.86(d, J=13.5 Hz, 1H), 3.72 (m, 4H), 2.74 (dt, J=15.0, 7.6 Hz, 1H), 2.63(dt, J=15.0, 7.5 Hz, 1H), 2.40 (d, J=1.9 Hz, 1H), 1.65 (m, 1H), 1.51 (m,2H), 1.35 (m, 2H), 1.21 (t, J=7.5 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.00(s, 9H); MS (APCI+) m/z 621 (M+H)⁺.

Example 229I(2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 229H (110 mg, 0.175 mmol) in tetrahydrofuran (0.5 mL),methanol (0.500 mL) and water (0.500 mL) was added lithium hydroxidehydrate (51.5 mg, 1.228 mmol) and the reaction was heated at 45° C. for16 hours. The solvent was removed under a stream of nitrogen. Water (1mL) was added to the crude material, and the mixture was extracted with5 mL heptane (discarded). The mixture was extracted with diethyl ether,and the extract was concentrated. Water was added (2 mL), and themixture was acidified with 1M aqueous HCl (10 drops) to pH˜6. Themixture was filtered to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.15 (s, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.09 (s, 2H), 6.87(d, J=2.4 Hz, 1H), 5.47 (s, 1H), 4.63 (s, 1H), 4.26-4.18 (m, 2H), 3.85(d, J=13.2 Hz, 1H), 3.76 (m, 4H), 3.40-3.29 (m, 1H), 2.28 (s, 3H),2.27-2.19 (m, 2H), 2.03-1.90 (m, 3H), 1.85 (pd, J=4.4, 2.2 Hz, 1H), 1.69(m, 1H), 1.54 (m, 2H), 1.37 (m, 3H), 0.99 (s, 9H); MS (APCI+) m/z 599(M+H)⁺.

Example 230(2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 230A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-1-Allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylatefrom Example 229E (200 mg, 0.472 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (185 mg, 0.684mmol) were dissolved in dry N,N-dimethylformamide (2.4 mL). Aftercooling in an ice bath, potassium 2-methylpropan-2-olate (0.684 mL,0.684 mmol) 1M solution in tetrahydrofuran was added dropwise over 4minutes. After 60 minutes, the mixture was acidified with 1M aqueous HCl(1.2 mL) and warmed to ambient temperature. The mixture was diluted withwater (20 mL) and extracted with dichloromethane. The extracts werepurified on a 24 g silica gel column and were eluted with a gradient of0-80% ethyl acetate/heptanes over 20 minutes to provide the titlecompound. ¹H NMR (501 MHz, DMSO-d₆) δ ppm 8.36 (dd, J=2.5, 1.2 Hz, 1H),7.91 (d, J=30.3 Hz, 1H), 7.07 (d, J=1.5 Hz, 3H), 5.73 (d, J=143.5 Hz,1H), 5.34-5.15 (m, 1H), 5.11 (s, 1H), 4.96-4.62 (m, 1H), 4.60-4.46 (m,3H), 4.42 (s, 3H), 4.33 (d, J=14.3 Hz, 1H), 4.10 (p, J=6.8 Hz, 2H), 3.87(d, J=14.6 Hz, 1H), 3.84 (s, 3H), 2.28 (s, 3H), 1.12 (t, J=7.1 Hz, 3H),1.02 (s, 9H); MS (APCI+) m/z 613 (M+H)⁺.

Example 230B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylatefrom Example 230A (180 mg, 0.294 mmol) in acetonitrile/water (4.29 mL,10:1) was added tetrakis(triphenylphosphine)palladium(0) (7.46 mg, 6.46μmol) and diethylamine (0.061 mL, 0.587 mmol) The mixture was stirred atambient temperature for 16 hours. Dichloromethane and water were added.The organic layer was washed with brine, dried over Na₂SO₄, filtered,and concentrated. The residue was purified by chromatography, eluting on12 g cartridge with a gradient 0-70% ethyl acetate/heptanes over 20minutes to provide the title compound. ¹H NMR (501 MHz, DMSO-d₆) δ ppm8.38-8.36 (m, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H),7.13-7.05 (m, 2H), 4.28 (d, J=14.0 Hz, 1H), 4.24 (dd, J=6.8, 4.6 Hz,1H), 4.16-4.07 (m, 2H), 4.06 (dd, J=5.1, 1.6 Hz, 1H), 3.84 (s, 3H), 3.75(d, J=14.0 Hz, 1H), 3.62 (t, J=6.7 Hz, 1H), 3.25 (t, J=7.1 Hz, 1H), 2.37(dd, J=6.4, 1.5 Hz, 1H), 2.26 (s, 3H), 1.18 (t, J=7.1 Hz, 3H), 0.95 (s,9H); MS (APCI+) m/z 529 (M+H)⁺.

Example 230C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylatefrom Example 230B (140 mg, 0.265 mmol) in dichloromethane (0.6 mL) at 0°C. was added triethylamine (0.166 mL, 1.191 mmol) followed by additionof (S)-tetrahydro-2H-pyran-2-carbonyl chloride (66.9 mg, 0.450 mmol) asa solution in 1 mL dichloromethane. After stirring for 15 minutes, themixture was quenched with 5 mL of saturated aqueous sodium bicarbonate.The crude material was chromatographed using a 12 g silica gel cartridgewith a gradient of 0-65% ethyl acetate/heptanes over a period of 20minutes to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.31 (t, J=1.5 Hz, 1H), 8.00 (s, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.09 (s,2H), 5.48 (s, 1H), 4.71 (s, 1H), 4.33-4.26 (m, 2H), 4.12 (qd, J=7.1, 4.1Hz, 2H), 3.88 (d, 4H), 3.76 (m, 2H), 2.43 (d, J=1.7 Hz, 1H), 2.32 (s,3H), 1.69 (m, 1H), 1.54 (m, 2H), 1.39 (m, 3H), 1.18 (t, J=7.1 Hz, 3H),1.03 (s, 9H); MS (APCI+) m/z 641 (M+H+).

Example 230D(2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(5-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 230C (130 mg, 0.203 mmol) in tetrahydrofuran (0.6 mL),methanol (0.600 mL) and water (0.600 mL) was added lithium hydroxidehydrate (59.6 mg, 1.419 mmol) and the reaction was heated at 45° C. for16 hours. The solvent was removed under a stream of nitrogen. Water (2mL) was added to the crude material, and the mixture was extracted with5 mL heptane (discarded). The desired product was extracted into diethylether, and the mixture was concentrated. Water (1 mL) was added and themixture was acidified with 1M aqueous HCl (14 drops mL) to pH˜6. Themixture was filtered to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.29 (d, J=2.4 Hz, 1H), 8.16 (s, 1H), 7.18 (d, J=2.4 Hz,1H), 7.06 (s, 2H), 5.48 (s, 1H), 4.62 (d, J=1.9 Hz, 1H), 4.31 (d, J=14.0Hz, 1H), 4.27 (d, J=6.1 Hz, 1H), 3.87 (m, 4H), 3.77 (d, J=11.3 Hz, 1H),2.49 (s, 1H), 2.28 (s, 3H), 1.69 (m, 1H), 1.55 (m, 2H), 1.37 (m, 3H),1.01 (s, 9H); MS (APCI+) m/z 613 (M+H)⁺.

Example 231(2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 231A (E)-ethyl2-((3-chloro-2-methylbenzylidene)amino)acetate

A mixture of ethyl 2-aminoacetate hydrochloride (4.8 g, 34.4 mmol) andmagnesium sulfate (8.28 g, 68.8 mmol) in dichloromethane (58 mL)(anhydrous) was treated with triethylamine (4.79 mL, 34.4 mmol). Themixture was stirred for 10 minutes and treated with3-chloro-2-methylbenzaldehyde (5.60 g, 34.4 mmol) (as a solution in 1 mLdichloromethane). The flask was capped and the mixture was stirred atambient temperature for 16 hours. The solid material was filtered, thefiltrate was washed with water, and the organic layer was dried withNa₂SO₄, filtered and concentrated to provide the title compound. ¹H NMR(400 MHz, Chloroform-d) δ ppm 8.63 (d, J=1.4 Hz, 1H), 7.84 (dd, J=7.8,1.3 Hz, 1H), 7.45 (dd, J=8.0, 1.3 Hz, 1H), 7.19 (t, J=7.9 Hz, 1H), 4.44(d, J=1.3 Hz, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.56 (s, 3H), 1.32 (t, J=7.1Hz, 3H).

Example 231B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.440 g, 0.584 mmol) and Cu(OTf)₂ (copper(II)trifluoromethanesulfonate, 0.118 g, 0.234 mmol) were dissolved intetrahydrofuran (46 mL) that had been sparged with a N₂ stream for 1hour. The resulting mixture was stirred for 1 hour at ambienttemperature (continued nitrogen sparge). (E)-ethyl2-((3-chloro-2-methylbenzylidene)amino)acetate (7 g, 29.2 mmol) in 5 mLtetrahydrofuran was added and the resulting solution was cooled to <5°C. in an ice water bath. Potassium 2-methylpropan-2-olate intetrahydrofuran (0.526 mL, 0.526 mmol) was added dropwise, followed byaddition of (E)-3,3-dimethyl-1-nitrobut-1-ene (Example 231A, 3.77 g,29.2 mmol) in 1 mL tetrahydrofuran over 2 minutes, maintaining atemperature less than 7° C. The reaction mixture was stirred for 2 hoursat 0° C. The mixture was quenched with 60 mL of saturated aqueousammonium chloride and 75 mL of ethyl acetate and warmed to ambienttemperature. The organic layer was separated and washed with saturatedaqueous ammonium chloride (2×30 mL) and brine and filtered through a padof silica gel. The mixture was concentrated, triturated with 100 mLheptane, and filtered to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.43 (d, J=7.8 Hz, 1H), 7.37 (dd, J=8.0, 1.2 Hz, 1H),7.17 (t, J=7.9 Hz, 1H), 5.29 (dd, J=7.1, 3.7 Hz, 1H), 4.71 (t, J=7.1 Hz,1H), 4.21 (qd, J=7.1, 4.5 Hz, 2H), 3.73 (dd, J=7.9, 6.9 Hz, 1H), 3.59(t, J=7.0 Hz, 1H), 3.12 (dd, J=8.0, 3.6 Hz, 1H), 2.41 (s, 3H), 1.26 (t,J=7.1 Hz, 3H), 0.96 (s, 9H); MS (APCI+) m/z 369 (M+H)⁺.

Example 231C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-nitropyrrolidine-1,2-dicarboxylate

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-nitropyrrolidine-2-carboxylatefrom Example 231B (5 g, 13.56 mmol) in toluene (16 mL) and saturatedaqueous NaHCO₃ (16 mL) was added allyl carbonochloridate (1.485 mL,13.56 mmol) dropwise at ambient temperature. The mixture was stirred atambient temperature for 16 hours. Ethyl acetate (30 mL) and water (25mL) were added and the organic layer was washed with brine andconcentrated. The resulting material was purified on a 24 g cartridgeeluting with a gradient of 0-100% ethyl acetate/heptanes over a periodof 20 minutes to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.81 (s, 1H), 7.30 (dd, J=8.1, 1.2 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H),5.78 (s, 1H), 5.67 (d, J=9.0 Hz, 1H), 5.57 (d, J=8.7 Hz, 1H), 5.14 (m,1H), 4.92-4.62 (m, 1H), 4.54 (d, J=3.4 Hz, 1H), 4.43 (s, 2H), 4.22 (q,J=7.0 Hz, 2H), 3.02 (d, J=2.9 Hz, 1H), 2.39 (s, 3H), 1.24 (t, J=7.1 Hz,3H), 0.99 (s, 9H); MS (APCI+) m/z 453 (M+H)⁺.

Example 231D (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-oxopyrrolidine-1,2-dicarboxylate

To potassium dichromate (8.77 g, 29.8 mmol) in 6N aqueous HCl (136 mL)was added zinc (9.96 g, 152 mmol) portionwise under a N₂ atmosphere atambient temperature. After the almost complete dissolution of zinc (˜2hours), the formed chromium(II) chloride was transferred via cannula toa refluxing solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-nitropyrrolidine-1,2-dicarboxylatefrom Example 231C (2.5 g, 5.52 mmol) in ethanol (115 mL) under N₂. Thereaction mixture was refluxed at 86° C. internally for 20 hours, andcooled. The mixture was concentrated and extracted with dichloromethanethree times. The combined organic phase was washed with brine and driedover Na₂SO₄, filtered, and concentrated. The residue (2.2 g) wassubjected to re-esterification. Acetyl chloride (2 mL, 28.13 mmol) wasadded slowly to an ice cooled flask containing ethanol (6 mL). After theaddition was complete, the mixture was stirred at ambient temperaturefor 5 minutes before pouring the resulting HCl/ethanol solution into aseparate flask containing the crude ester/acid mixture. The mixture washeated at 65° C. for an additional hour, cooled to ambient temperature,and concentrated. The residue was purified on a 24 g cartridge elutingwith a gradient of 0-70% ethyl acetate/heptanes over a period of 20minute to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.75 (d, J=7.8 Hz, 1H), 7.33 (dd, J=8.0, 1.2 Hz, 1H), 7.17 (t, J=7.9 Hz,1H), 5.71 (d, J=95.0 Hz, 1H), 5.39 (s, 1H), 5.18 (m, 1H), 4.79 (d,J=97.1 Hz, 1H), 4.57 (s, 1H), 4.45 (m, 2H), 4.18 (qd, J=7.2, 1.5 Hz,2H), 2.71 (d, J=5.4 Hz, 1H), 2.40 (s, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.01(s, 9H); MS (APCI+) m/z 422 (M+H)⁺.

Example 231E (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

(2S,3R,5S)-1-Allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-oxopyrrolidine-1,2-dicarboxylatefrom Example 231D (1.38 g, 3.27 mmol) was dissolved in ethanol (16.35mL) and sodium borohydride (0.247 g, 6.54 mmol) was added after coolingthe reaction to <−10° C. in an ice acetone bath. The ice bath wasremoved and the mixture was allowed to warm to room temperature over 20minutes. The mixture was concentrated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate for 30 minutes. Theorganics were concentrated and purified via flash chromatography,eluting with 0-80% ethyl acetate/heptanes on 24 g silica gel cartridgeover a period of 20 minutes to give crude product which was furtherpurified by eluting with 0-2% methanol/dichloromethane over a period of20 minute on a 24 g silica gel cartridge to provide the title compound.¹H NMR (501 MHz, DMSO-d₆) δ ppm 7.91 (s, 1H), 7.28-7.19 (m, 1H), 7.11(t, J=7.9 Hz, 1H), 5.70 (d, J=120.3 Hz, 1H), 5.30-4.98 (m, 2H),4.97-4.59 (m, 2H), 4.41 (s, 2H), 4.33 (s, 1H), 4.25 (s, 1H), 4.13 (qd,J=7.1, 2.4 Hz, 2H), 2.31 (s, 3H), 2.20 (s, 1H), 1.21 (t, J=7.1 Hz, 3H),0.95 (s, 9H); MS (APCI+) m/z 424 (M+H)⁺.

Example 231F (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-1-Allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylatefrom Example 231E (200 mg, 0.472 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (175 mg, 0.684 mmol) weredissolved in dry N,N-dimethylformamide (2.4 mL). After cooling in an icebath, potassium 2-methylpropan-2-olate (0.684 mL, 0.684 mmol, 1 Msolution in tetrahydrofuran) was added dropwise over 2 minutes. After 60minutes, the reaction was acidified with 1M aqueous HCl (0.17 mL) andwarmed to ambient temperature. The mixture was diluted with water (10mL) and was extracted with dichloromethane. The extracts were loadedonto a 12 g silica gel column and were eluted with 0-70% ethylacetate/heptanes over 20 minutes to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.91 (d, J=19.7 Hz, 1H), 7.74 (d, J=2.4 Hz,1H), 7.25 (d, J=7.9 Hz, 1H), 7.11 (t, J=7.9 Hz, 1H), 6.72 (d, J=2.4 Hz,1H), 5.70 (d, J=111.3 Hz, 1H), 5.21 (m, 3H), 4.96-4.57 (m, 1H), 4.48 (m,2H), 4.36 (s, 2H), 4.25 (d, J=13.6 Hz, 1H), 4.13-3.96 (m, 2H), 3.90 (d,J=13.5 Hz, 1H), 3.71 (s, 3H), 3.28-3.20 (m, 1H), 2.31 (s, 3H), 2.15(dddt, J=6.4, 4.9, 3.6, 1.9 Hz, 2H), 1.99-1.84 (m, 2H), 1.84-1.73 (m,2H), 1.05 (t, J=7.1 Hz, 3H), 1.00 (s, 9H); MS (APCI+) m/z 599 (M+H)⁺.

Example 231G (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylatefrom Example 231F (146 mg, 0.244 mmol) in acetonitrile/water (4.18 mL,10:1) was added tetrakis(triphenylphosphine)palladium(0) (6.19 mg, 5.36μmol) and diethylamine (0.050 mL, 0.487 mmol) The mixture was stirred atambient temperature for 16 hours. Dichloromethane and water were added,and the organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by chromatography,eluting on 12 g cartridge with a gradient of 0-70% ethylacetate/heptanes over 20 minutes to provide the title compound. ¹H NMR(501 MHz, DMSO-d₆) δ ppm 7.78 (d, J=2.4 Hz, 1H), 7.64 (dd, J=7.8, 1.3Hz, 1H), 7.31 (dd, J=8.0, 1.3 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 6.85 (d,J=2.4 Hz, 1H), 4.25 (dd, J=7.8, 4.5 Hz, 1H), 4.19 (d, J=13.2 Hz, 1H),4.16-4.07 (m, 2H), 4.02 (dd, J=4.6, 1.5 Hz, 1H), 3.77 (d, J=13.2 Hz,1H), 3.72 (s, 3H), 3.60 (t, J=7.0 Hz, 1H), 3.17 (t, J=7.7 Hz, 1H), 2.33(d, J=2.2 Hz, 1H), 2.32 (s, 3H), 2.23-2.13 (m, 2H), 2.01-1.87 (m, 3H),1.87-1.78 (m, 1H), 1.18 (t, J=7.1 Hz, 3H), 0.95 (s, 9H); MS (APCI+) m/z515 (M+H)⁺.

Example 231H (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)pyrrolidine-2-carboxylatefrom Example 231G (98 mg, 0.190 mmol) in dichloromethane (0.6 mL) at 0°C. was added triethylamine (0.119 mL, 0.856 mmol) followed by addition(S)-tetrahydro-2H-pyran-2-carbonyl chloride (48.1 mg, 0.323 mmol) as asolution in 1 mL dichloromethane. After stirring for 15 minutes, thereaction was quenched with 5 mL of saturated aqueous sodium bicarbonate.The crude material was chromatographed using a 24 g silica gelcartridge, eluting with a gradient of 0-65% ethyl acetate/heptanes overa period of 20 minutes to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.00 (d, J=7.8 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.26 (d,J=7.1 Hz, 1H), 7.10 (m, 1H), 6.88 (d, J=2.4 Hz, 1H), 5.57 (s, 1H), 4.69(s, 1H), 4.28 (d, J=5.9 Hz, 1H), 4.21 (d, J=13.1 Hz, 1H), 4.10 (qd,J=7.1, 0.9 Hz, 2H), 3.87 (d, J=13.1 Hz, 1H), 3.76 (m, 4H), 3.34 (p,J=8.4 Hz, 1H), 2.42 (t, J=1.4 Hz, 1H), 2.37 (m, 4H), 2.31-2.19 (m, 2H),2.05-1.90 (m, 3H), 1.90-1.81 (m, 1H), 1.67 (m, 1H), 1.51 (m, 2H), 1.38(m, 3H), 1.14 (t, J=7.0 Hz, 3H), 1.02 (s, 9H); MS (APCI+) m/z 627(M+H)⁺.

Example 231I(2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 231H (88 mg, 0.140 mmol) in tetrahydrofuran (0.45 mL),methanol (0.450 mL) and water (0.450 mL) was added lithium hydroxidehydrate (41.2 mg, 0.982 mmol) and the reaction was heated at 45° C. for40 hours. The solvent was removed under a stream of nitrogen. Water (1mL) was added to the crude material, and the mixture was extracted with5 mL heptane (discarded). The desired product was extracted into diethylether and the organics were concentrated. Water (2 mL) was added, andthe mixture was acidified with 1M aqueous HCl (8 drops) to pH˜6, andfiltered to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.25 (d, J=7.9 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H),7.07 (m, 1H), 6.78 (d, J=2.4 Hz, 1H), 5.57 (s, 1H), 4.56 (s, 1H), 4.25(d, J=13.5 Hz, 2H), 3.94-3.86 (m, 1H), 3.80 (s, 1H), 3.77 (s, 3H), 3.33(q, J=8.4 Hz, 1H), 2.59 (s, 1H), 2.34 (s, 3H), 2.30-2.16 (m, 2H),2.03-1.79 (m, 4H), 1.68 (m, 1H), 1.54 (m, 2H), 1.37 (s, 3H), 1.00 (s,9H); MS (APCI+) m/z 599 (M+H)⁺.

Example 232(2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 232A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-1-Allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-hydroxypyrrolidine-1,2-dicarboxylatefrom Example 231E (200 mg, 0.472 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (185 mg, 0.684mmol) were dissolved in dry N,N-dimethylformamide (2.4 mL). Aftercooling in an ice bath, potassium 2-methylpropan-2-olate (0.684 mL,0.684 mmol) as a 1 M solution in tetrahydrofuran was added dropwise over4 minutes. After 60 minutes, the reaction was acidified with 1M aqueousHCl (1.2 mL) and warmed to ambient temperature. The mixture was dilutedwith water (20 mL) and extracted with dichloromethane. The extracts wereloaded onto a 24 g silica gel column eluting with a gradient of 0-80%ethyl acetate/heptanes over 20 minutes to provide the title compound. ¹HNMR (501 MHz, DMSO-d₆) δ ppm 8.36 (dd, J=2.6, 1.2 Hz, 1H), 7.89 (d,J=26.3 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.07 (s, 1H), 6.98 (d, J=2.4 Hz,1H), 5.72 (d, J=140.0 Hz, 1H), 5.19 (m, 2H), 4.99-4.63 (m, 1H), 4.50 (s,2H), 4.43 (s, 2H), 4.34 (d, J=14.2 Hz, 1H), 4.06 (qq, J=7.4, 3.9 Hz,2H), 3.96 (d, J=14.2 Hz, 1H), 3.85 (s, 3H), 2.51 (s, 1H), 2.34 (s, 3H),1.07 (t, J=7.1 Hz, 3H), 1.02 (s, 9H); MS (APCI+) m/z 613 (M+H)⁺.

Example 232B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylatefrom Example 232A (190 mg, 0.310 mmol) in acetonitrile/water (4.29 mL,10:1) was added tetrakis(triphenylphosphine)palladium(0) (7.88 mg, 6.82μmol) and diethylamine (0.064 mL, 0.620 mmol) The mixture was stirred atambient temperature for 16 hours. Dichloromethane and water were added,and the organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The mixture was purified by chromatography,eluting on 12 g cartridge with a gradient of 0-70% ethylacetate/heptanes over 20 minutes to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.37 (d, J=2.1 Hz, 1H), 7.63 (dd, J=7.5, 1.3Hz, 1H), 7.24 (dd, J=8.0, 1.3 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 7.08 (t,J=7.9 Hz, 1H), 4.32-4.24 (m, 2H), 4.17-4.05 (m, 3H), 3.84 (s, 4H), 3.62(t, J=7.0 Hz, 1H), 3.21 (t, J=7.5 Hz, 1H), 2.36 (dd, J=6.6, 1.4 Hz, 1H),2.33 (s, 3H), 1.18 (t, J=7.1 Hz, 3H), 0.96 (s, 9H); MS (APCI+) m/z 529(M+H)⁺.

Example 232C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylatefrom Example 232B (132 mg, 0.250 mmol) in dichloromethane (0.6 mL) at 0°C. was added triethylamine (0.157 mL, 1.123 mmol) followed by additionof (S)-tetrahydro-2H-pyran-2-carbonyl chloride (63.0 mg, 0.424 mmol) ofas a solution in 1 mL dichloromethane. After stirring for 15 minutes,the mixture was quenched with 5 mL of saturated aqueous sodiumbicarbonate. The crude material was chromatographed using a 12 g silicagel cartridge with a gradient of 0-65% ethyl acetate/heptanes over aperiod of 20 minutes to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.30 (d, J=1.4 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.20 (m,2H), 7.05 (m, 1H), 5.60 (s, 1H), 4.71 (s, 1H), 4.33 (d, J=6.0 Hz, 1H),4.30 (d, J=13.7 Hz, 1H), 4.09 (qd, J=7.1, 2.1 Hz, 2H), 3.88 (d, 4H),3.76 (m, 2H), 2.43 (d, J=1.9 Hz, 1H), 2.39 (s, 3H), 1.68 (d, J=11.9 Hz,1H), 1.52 (m, 2H), 1.38 (s, 3H), 1.14 (m, 3H), 1.04 (s, 9H); MS (APCI+)m/z 641 (M+H)⁺.

Example 232D(2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(3-chloro-2-methylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 232C (121 mg, 0.189 mmol) in tetrahydrofuran (0.55 mL),methanol (0.550 mL) and water (0.550 mL) was added lithium hydroxidehydrate (55.4 mg, 1.321 mmol) and the reaction was heated at 45° C. for40 hours. The solvent was removed under a stream of nitrogen. Water (2mL) was added to the crude material, and the mixture was extracted with5 mL heptane (discarded). The desired product was extracted into diethylether, and concentrated. Water (2 mL) was added, and the mixture wasacidified with 1M aqueous HCl (13 drops) to pH˜6. The precipitate wasfiltered to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.29 (d, J=2.5, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H),7.14 (d, J=2.5 Hz, 1H), 7.04 (m, 1H), 5.60 (s, 1H), 4.62 (d, J=2.0 Hz,1H), 4.35-4.31 (m, 2H), 4.30 (s, 1H), 3.93 (d, J=13.9 Hz, 1H), 3.89 (s,3H), 3.78 (d, J=11.3 Hz, 1H), 2.54 (s, 1H), 2.37 (s, 3H), 1.68 (s, 1H),1.53 (m, 2H), 1.37 (m, 3H), 1.03 (s, 9H); MS (APCI+) m/z 613 (M+H⁺).

Example 233(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188 substituting3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine (Intermediate 10) forIntermediate 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.06-8.01 (m, 1H), 7.91(d, J=2.7 Hz, 1H), 7.17-7.13 (m, 1H), 5.53 (s, 2H), 4.65-4.59 (m, 1H),4.23 (d, J=5.9 Hz, 1H), 4.17 (d, J=13.1 Hz, 1H), 3.78 (d, J=8.4 Hz, 2H),3.75 (s, 3H), 3.35 (s, 1H), 2.63 (s, 6H), 2.33 (s, 3H), 1.68-1.28 (m,6H), 1.19 (s, 9H), 1.00 (s, 9H); MS (ESI+) m/z 567 (M+H)⁺.

Example 234(2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)phenyl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 234A

2-bromo-1-methoxy-4-(trifluoromethyl)benzene-d3A mixture of2-bromo-4-(trifluoromethyl)phenol (5.0 g, 20.75 mmol) and potassiumcarbonate (5.73 g, 41.5 mmol) in N,N-dimethylformamide (10 mL) stirredat room temperature for 30 minutes, and iodomethane-d₃ (4.51 g, 31.1mmol) was added. The reaction was stirred at room temperature overnight.The solvent was removed and residue was dissolved in methanol, filteredand purified by reverse phase HPLC with trifluoroacetic acid method toprovide the title compound.

Example 234B 2-(d₃-methoxy-5-(trifluoromethyl)benzoate

2-Bromo-1-methoxy-4-(trifluoromethyl)benzene-d₃ (5 g, 19.38 mmol), andPd-dppf ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),Heraeus) (0.1395 g, 0.191 mmol) were added in a 50 mL Hast C reactor.Methanol (15 mL) and triethylamine (5 mL, 35.9 mmol) were added and thereactor was degassed with nitrogen several times. Carbon monoxide wasadded and the mixture was heated to 100° C. for 16 hours at 60 psi. Thereaction mixture was concentrated and purified via an 80 g silica gelcartridge, eluting with ethyl acetate in heptane at 0-40% gradient toprovide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.08(d, J=2.4 Hz, 1H), 7.73 (dd, J=8.8, 2.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H),3.92 (s, 3H).

Example 234C (2-(d₃-methoxy-5-(trifluoromethyl)phenyl)(d₂)methanol

To methyl 2-(d₃-methoxy-5-(trifluoromethyl)benzoate (3.7148 g, 15.66mmol) in tetrahydrofuran (20 mL) cooling in an ice bath was added sodiumborodeuteride (0.656 g, 15.66 mmol) portionwise. The mixture was stirredfor 10 minutes in an ice bath, warmed to room temperature, and heated toreflux at 67° C. for 2 hours. To the mixture was added CH₃OD (4 mL)slowly, and the reaction mixture was stirred at room temperatureovernight, when more NaBD4 (0.328 g, 7.83 mmol) and 1 mL of CH₃OD wereadded. Stirring was continued for 2 hours, before the reaction wasquenched with saturated aqueous NH₄Cl (20 mL). Ethyl acetate (60 mL) wasadded into the reaction mixture. The organic layer was washed with brineand dried over sodium sulfate, filtered, concentrated and purified byflash chromatography on a 40 g silica gel cartridge, eluting with ethylacetate in heptane at 0-20% gradient to provide the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.65 (d, J=2.4 Hz, 1H), 7.57 (ddd, J=8.5,2.5, 0.9 Hz, 1H), 7.14-7.07 (m, 1H), 5.21 (s, 1H); MS (DCI+) m/z 229.1(M+NH₄)⁺.

Example 234D2-(bromo-d₂-methyl)-1-(d₃)-methoxy-4-(trifluoromethyl)benzene

Into a 200 mL 3 neck round bottom flask was added triphenylphosphine(3.92 g, 14.96 mmol) and dichloromethane (57.5 mL) The resultingsolution was cooled in an ice water bath to <5° C. and1-bromo-5-methylenepyrrolidin-2-one (2.63 g, 14.96 mmol) was addedportionwise over 3-5 minutes, maintaining an internal temperature<10° C.After stirring for 30 minutes,(2-(d₃-methoxy-5-(trifluoromethyl)phenyl)(d₂)methanol (2.43 g, 11.51mmol) in dichloromethane (5 mL) was added slowly into it, maintaining aninternal temperature<10° C. for 1 hour. Saturated aqueous NH₄Cl (6 mL)was added and the solvent was removed. The residue was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer was dried over sodium sulfate, filtered, and concentrated.Purification via chromatography on a 40 g silica gel cartridge, elutingwith ethyl acetate in heptane using a 0-30% gradient provided the titlecompound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.65-7.55 (m, 2H), 6.97(d, J=8.6 Hz, 1H).

Example 234E(2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)phenyl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 188B, 70 mg, 0.168 mmol) and2-(bromomethyl-d₂)-1-methoxy-d₃-4-(trifluoromethyl)benzene (Example234D, 68.9 mg, 0.251 mmol) in N,N-dimethylformamide (2 mL) cooling in anice bath, was added potassium 2-methylpropan-2-olate (28.2 mg, 0.251mmol) (0.22 mL, 1.0M in tetrahydrofuran) dropwise. The mixture wasstirred in an ice bath for 20 minutes, and was allowed to warm toambient temperature. Dichloromethane (20 mL) and saturated aqueous NH₄Cl(5 mL) were added. The organic layer was washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified viachromatography, eluting with ethyl acetate in heptane, 0-40% gradient toprovide the intermediate ester; which was dissolved in methanol (2 mL)and 6M aqueous LiOH (0.5 mL). The mixture was stirred at 45° C. for 4hours. The pH was adjusted to 1˜2. Purification via chromatography on a12 g silica gel cartridge, eluting with ethyl acetate/methanol (9:1) inheptane at 0-45% gradient provided the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.02 (q, J=3.8, 2.8 Hz, 1H), 7.43 (dd, J=8.7, 2.4 Hz,1H), 7.07 (s, 3H), 6.98 (d, J=8.6 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 5.54(s, 1H), 4.64-4.60 (m, 1H), 4.22 (d, J=5.9 Hz, 1H), 3.76 (d, J=11.3 Hz,1H), 3.37 (s, 2H), 2.63 (s, 1H), 2.31 (s, 3H), 1.70-1.24 (m, 6H), 1.00(s, 9H); MS (ESI+) m/z 583 (M+H)⁺.

Example 235(2S,3R,4S,5S)-3-tert-butyl-4-{[(5-tert-butyl-2-methoxyphenyl)(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 235A 2-bromo-4-(tert-butyl)-1-methoxybenzene

To 2-bromo-4-(tert-butyl)phenol [CAS#2198-66-5] (5 g, 21.82 mmol) andpotassium carbonate (6.03 g, 43.6 mmol) in N,N-dimethylformamide (12 mL)was added iodomethane (2.72 mL, 43.6 mmol) slowly at room temperature.The mixture was stirred at room temperature for 10 minutes and 40° C.overnight. The mixture was filtered and the cake was washed with CH₂Cl₂.The combined organics were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified via chromatographyon a 40 g silica gel cartridge, eluting with ethyl acetate in heptane at0-25% gradient to provide the title compound. MS (APCI+) m/z 244 (M+H)⁺.

Example 235B methyl 5-(tert-butyl)-2-methoxybenzoate

Example 235A (5 g, 20.56 mmol) in methanol (15 mL) and triethylamine(2.87 mL, 20.56 mmol) were added to Pd-dppf([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, Heraeus, CAS#95464-05-4)) (870 mg, 1.189 mmol) in a 250mL pressure bottle under argon. The mixture was pressurized with 70 psiof carbon monoxide and stirred at 100° C. for 16 hours. The solvent wasremoved and the residue was purified via chromatography, eluting withethyl acetate in heptane at a 0-30% gradient to provide the titlecompound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.80 (d, J=2.6 Hz, 1H),7.49 (dd, J=8.8, 2.7 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 3.89(s, 3H), 1.32 (s, 9H); MS (APCI+) m/z 223 (M+H)⁺.

Example 235C (5-(tert-butyl)-2-methoxyphenyl)-dideuterio methanol

To Example 235B (1.0 g, 4.50 mmol) in tetrahydrofuran (5 mL) andmethanol (5.00 mL) cooling in an ice bath was added sodium borodeuteride(0.377 g, 9.00 mmol) slowly. The mixture was stirred at ambienttemperature for 2 hours, and saturated aqueous NH₄Cl (2 mL) and ethylacetate (30 mL) were added to the reaction mixture. The mixture waswashed with brine, dried over sodium sulfate, filtered, andconcentrated. Purification via chromatography on a 40 g silica gelcartridge, eluting with ethyl acetate in heptane at 0-30% gradientprovided the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm7.38-7.27 (m, 2H), 6.86 (dd, J=8.5, 1.4 Hz, 1H), 3.88 (d, J=1.0 Hz, 3H),2.36 (s, 1H), 1.34 (s, 9H).

Example 235D 2-(dideuterio-bromomethyl)-4-(tert-butyl)-1-methoxybenzene

To triphenylphosphine (695 mg, 2.65 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (472 mg,2.65 mmol) portionwise. The mixture was stirred for 30 minutesmaintaining an internal temperature<10° C. Example 235C (400 mg, 2.038mmol) in dichloromethane (2 mL) was added slowly. The mixture wasstirred in an ice bath for 1 hour and was allowed to warm to ambienttemperature. Saturated aqueous NH₄Cl (10 mL) and dichloromethane (10 mL)were added. The organic layer was washed with saturated aqueous NaHCO₃and brine, dried over MgSO₄, filtered and concentrated. Purification viachromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptane at 0-30% gradient provided the title compound. MS(APCI+) m/z 179 (M-Br)⁺.

Example 235E(2S,3R,4S,5S)-3-tert-butyl-4-{[(5-tert-butyl-2-methoxyphenyl)(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To Example 188B (70 mg, 0.168 mmol) and Example 235D (47.8 mg, 0.184mmol) in N,N-dimethylformamide (2 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (0.22 mL, 1.0M in tetrahydrofuran) was addeddropwise. The mixture was stirred in an ice bath for 20 minutes, andstirred at room temperature for 30 minutes. Dichloromethane (20 mL) andsaturated aqueous NH₄Cl (10 mL) were added. The organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified via chromatography, eluting with ethyl acetate in heptane,0-40% gradient to yield (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxy-dideuteriobenzyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate,which was dissolved in methanol (2 mL) and 6M aqueous LiOH (0.5 mL). Themixture was stirred at 45° C. for 4 hours. The solvent was removed andresidue was adjusted pH to 1˜2 by adding 2M aqueous HCl. The mixture wasextracted with dichloromethane (10 mL×3). The combined organics werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified via HPLC with the trifluoroacetic acid method toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.06-8.01(m, 1H), 7.12 (d, J=2.6 Hz, 1H), 7.10-7.03 (m, 3H), 6.85 (d, J=2.6 Hz,1H), 6.72 (d, J=8.6 Hz, 1H), 5.50 (s, 1H), 4.59 (s, 1H), 4.19 (d, J=5.9Hz, 1H), 3.75 (d, J=11.9 Hz, 1H), 3.61 (s, 3H), 3.39 (d, J=32.7 Hz, 2H),2.44 (d, J=1.6 Hz, 1H), 2.32 (s, 3H), 1.69-1.27 (m, 6H), 1.17 (s, 9H),0.97 (s, 9H); MS (ESI+) m/z 568.3 (M+H)⁺.

Example 236(2S,3R,4S,5S)-3-tert-butyl-4-[(2-chloro-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 236A 3-(bromomethyl)-2-chloro-5,7-dimethylquinoline

To triphenylphosphine (355 mg, 1.353 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (241 mg,1.353 mmol) portionwise. The mixture was stirred for 30 minutes,maintaining an internal temperature<10° C., and(2-chloro-5,7-dimethylquinolin-3-yl)methanol [CAS#1017464-08-2] (200 mg,0.902 mmol) in dichloromethane (6 mL) was added portionwise at <10° C.The mixture was stirred in an ice bath for 1 hour and allowed to warm toambient temperature. Saturated aqueous NH₄Cl (2 mL) was added and thesolvent was removed. The residue was partitioned between ethyl acetateand saturated aqueous sodium bicarbonate. The organics were dried oversodium sulfate, filtered, and concentrated. Purification viachromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptane using a 0-30% gradient provided the title compound.¹H NMR (400 MHz, Chloroform-d) δ ppm 8.40-8.32 (m, 1H), 7.70-7.64 (m,1H), 7.27 (d, J=3.2 Hz, 1H), 4.82 (d, J=42.9 Hz, 2H), 2.69 (dd, J=3.8,0.8 Hz, 3H), 2.54 (dd, J=2.2, 0.9 Hz, 3H), 2.54 (s, 3H); MS (ESI+) m/z285 (M+H)⁺.

Example 236B(2S,3R,4S,5S)-3-tert-butyl-4-[(2-chloro-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188, substituting Example 236A for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.16-8.08 (m, 1H), 7.85 (d, J=1.1 Hz, 1H), 7.45 (s,1H), 7.25 (s, 1H), 7.10-6.99 (m, 3H), 5.58 (s, 1H), 4.65 (d, J=5.0 Hz,1H), 4.43 (dd, J=13.6, 1.1 Hz, 1H), 4.38 (d, J=5.7 Hz, 1H), 3.97 (dd,J=13.5, 1.1 Hz, 1H), 3.88 (s, 1H), 3.76 (d, J=11.2 Hz, 2H), 2.54 (s,3H), 2.43 (s, 3H), 2.37 (s, 3H), 2.32 (s, 1H), 1.69-1.33 (m, 6H), 1.03(d, J=7.4 Hz, 9H); MS (ESI+) m/z 593.3 (M+H)⁺.

Example 237(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 237A (2-chloro-5,8-dimethylquinolin-3-yl)methanol

To 2-chloro-5,8-dimethylquinoline-3-carbaldehyde [cas 323196-71-0] (250mg, 1.138 mmol) in ethanol (5 mL) cooling in an ice bath, sodiumborohydride (64.6 mg, 1.707 mmol) was added in portions. The mixture wasstirred in an ice bath for 30 minutes. Saturated aqueous NH₄Cl (2 mL)was added and the solvent was removed under reduced pressure. Theresidue was dissolved in dichloromethane (20 mL). The mixture was washedwith brine, dried over sodium sulfate, filtered, and concentrated toprovide the title compound. MS (APCI+) m/z 222.2 (M+H)⁺.

Example 237B (2-methoxy-5,8-dimethylquinolin-3-yl)methanol

Example 237A (210 mg, 0.947 mmol) was added to a solution of sodiummethoxide (6.83 mmol prepared from Na (143 mg) in methanol (5 mL)). Thereaction mixture was refluxed overnight. The solvent was removed andwater was added. The mixture was extracted with ethyl acetate, driedover MgSO₄, filtered, and concentrated. The residue was purified bychromatography on a 10 g silica gel cartridge, eluting with ethylacetate in heptane, at a 0-40% gradient to provide the title compound.MS (APCI+) m/z 218.2 (M+H)⁺.

Example 237C 3-(bromomethyl)-2-methoxy-5,8-dimethylquinoline

The title compound was prepared according to the procedure described inExample 236A, substituting Example 237B for(2-chloro-5,7-dimethylquinolin-3-yl)methanol. MS (APCI+) m/z 282 (M+H)⁺.

Example 237D(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188, substituting Example 237C for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.13-8.09 (m, 1H), 7.72 (d, J=1.3 Hz, 1H), 7.65-7.47(m, 2H), 7.29 (d, J=7.2 Hz, 1H), 7.06 (d, J=6.4 Hz, 2H), 5.56 (s, 1H),4.65 (s, 1H), 4.39-4.30 (m, 2H), 3.97 (d, J=1.3 Hz, 1H), 3.93 (s, 3H),3.76 (d, J=11.3 Hz, 2H), 3.36 (s, 1H), 2.53 (s, 4H), 2.46 (s, 3H), 2.33(s, 3H), 1.71-1.30 (m, 6H), 1.03 (s, 9H); MS (ESI+) m/z 589.2 (M+H)⁺.

Example 238(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 238A 3-(bromomethyl)-2-methoxy-5,7-dimethylquinoline

The title compound was prepared according to the procedure described inExample 237 B-C, substituting(2-chloro-5,7-dimethylquinolin-3-yl)methanol for(2-chloro-5,8-dimethylquinolin-3-yl)methanol. ¹H NMR (400 MHz,Chloroform-d) δ ppm 8.11 (t, J=1.0 Hz, 1H), 7.66-7.44 (m, 1H), 7.09 (s,1H), 4.80 (d, J=6.3 Hz, 2H), 4.14 (d, J=0.9 Hz, 3H), 2.63 (s, 3H), 2.50(s, 3H), 2.40 (t, J=6.5 Hz, 1H); MS (ESI+) m/z 218.1 (M+H)⁺.

Example 238B(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188, substituting Example 238A for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.08 (dd, J=7.2, 2.6 Hz, 1H), 7.26 (s, 1H), 7.18 (d,J=7.1 Hz, 2H), 7.13 (d, J=4.4 Hz, 3H), 5.56 (s, 1H), 4.66 (s, 1H),4.36-4.30 (m, 1H), 4.30-4.24 (m, 1H), 3.94 (dd, J=13.9, 1.3 Hz, 1H),3.91 (s, 3H), 3.77 (d, J=11.4 Hz, 1H), 3.39 (m, 2H), 2.54 (s, 3H),2.52-2.50 (m, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 1.70-1.30 (m, 6H), 1.02(s, 9H); MS (ESI+) m/z 589.3 (M+H)⁺.

Example 239(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 239A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.168 g, 0.223 mmol) and copper (I) triflate dimer, benzene complex(0.049 g, 0.097 mmol) were dissolved in tetrahydrofuran (43.1 mL) thathad been sparged with a nitrogen stream for 1 hour. The resultingmixture was stirred for 1 hour at ambient temperature, and (E)-ethyl2-((2-methoxybenzylidene)amino)acetate (Core 2A) (5.15 g, 23.28 mmol)was added as a solution in 5 mL of tetrahydrofuran and the resultingsolution was cooled to <5° C. in an ice water bath. Potassium2-methylpropan-2-olate, 1M in tetrahydrofuran (0.155 mL, 0.155 mmol) wasadded dropwise, followed by addition of(E)-3,3-dimethyl-1-nitrobut-1-ene (2.505 g, 19.40 mmol) over 10 minutes,maintaining a temperature less than 6° C. After 20 minutes in the icebath, additional potassium 2-methylpropan-2-olate was added, 1M intetrahydrofuran (0.155 mL, 0.155 mmol), and the mixture was stirred inthe ice bath for another 30 minutes. The mixture was poured intosaturated aqueous ammonium chloride (50 mL) and diluted with ethylacetate (250 mL). The organic layer was washed with saturated aqueousammonium chloride, filtered through a plug of diatomaceous earth toppedwith silica gel, and dried over sodium sulfate. After filtration, themixture was concentrated. Heptanes and pentane were added and thesolvent was removed in vacuo. Heptane (10 mL) was added and the mixturewas cooled in an ice bath. The mixture was concentrated, taken up inheptane (75 mL), brought to reflux, and decanted while hot. The heptanewas reduced in volume and the crude material was purified using an 80 gsilica gel cartridge eluting with 0-50% ethyl acetate/heptanes over 25minutes to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δppm 7.33-7.29 (m, 1H), 7.28-7.24 (m, 1H), 6.98 (td, J=7.6, 1.1 Hz, 1H),6.90 (dd, J=8.3, 1.0 Hz, 1H), 5.37 (dd, J=5.7, 2.5 Hz, 1H), 4.63-4.54(m, 1H), 4.34 (qd, J=7.1, 1.5 Hz, 2H), 3.92 (s, 3H), 3.84-3.75 (m, 1H),3.45-3.34 (m, 1H), 2.92 (dd, J=7.3, 2.5 Hz, 1H), 1.37 (t, J=7.2 Hz, 3H),1.08 (s, 9H); MS (APCI+) m/z 351 (M+H)⁺.

Example 239B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-nitro-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a cooled (ice bath) solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-nitropyrrolidine-2-carboxylate fromExample 239A (410 mg, 1.170 mmol) in dichloromethane (4.756 mL) wasadded triethylamine (0.734 mL, 5.27 mmol) followed by the addition of(S)-tetrahydro-2H-pyran-2-carbonyl chloride (362 mg, 2.436 mmol) of as asolution in 2 mL dichloromethane. After stirring for 15 minutes, themixture was quenched with 10 mL of saturated aqueous sodium bicarbonate.The aqueous layer was extracted with 10 mL dichloromethane. The combinedorganics were reduced in volume and the crude material waschromatographed using a 40 g silica gel cartridge with a gradient of0-80% ethyl acetate/heptanes over a period of 20 minutes to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.76 (d, J=7.7 Hz, 1H),7.25 (t, J=7.8 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.88 (t, J=7.6 Hz, 1H),6.12 (s, 1H), 5.42 (dd, J=8.7, 2.7 Hz, 1H), 4.80 (s, 1H), 4.22 (q, J=7.1Hz, 2H), 3.84 (s, 3H), 3.81-3.71 (m, 1H), 2.93 (td, J=3.4, 0.7 Hz, 2H),1.73-1.66 (m, 1H), 1.54 (d, J=12.3 Hz, 1H), 1.47-1.32 (m, 3H), 1.27 (t,J=7.1 Hz, 3H), 1.00 (s, 9H), 0.92 (s, 1H), 0.89-0.80 (m, 1H); MS (APCI+)m/z 463 (M+H)⁺.

Example 239C (2S,3R,5S)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-oxo-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

A 50 mL flask was charged DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)(0.616 mL, 4.09 mmol), and carbon disulfide (0.352 mL, 5.84 mmol) in 1.4mL CH₃CN and the mixture was stirred at ambient temperature for 30minutes. The resulting mixture was cooled to 0° C. in an ice bath and(2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-nitro-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 239B (0.540 g, 1.167 mmol) in 1.4 mL of CH₃CN was addeddropwise. The reaction was warmed to room temperature over 1 hour, andstirred at ambient temperature for 1 hour. Additional carbon disulfide(0.352 mL, 5.84 mmol) was added. CH₃CN (15 mL) was added and 6.0 mLaqueous 20% H₃PO₄ solution was added to hydrolyze the resulting imine.The mixture was stirred for 3 hours at ambient temperature. Methyltert-butyl ether (20 mL) and 20 mL brine were added. The organic layerwas washed with 18 mL of brine with the addition of 18 mL methyltert-butyl ether. The mixture was filtered and concentrated. AdditionalCH₃CN (15 mL) and 6.0 mL aqueous 20% H₃PO₄ solution were added and themixture was stirred at ambient temperature for 2 hours more. The mixturewas extracted again as described, and the crude material was adsorbedonto silica gel, and concentrated. The residue was chromatographed usinga 24 g silica gel cartridge with a gradient of 0-60% ethylacetate/heptanes over a period of 20 minutes to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.63 (dd, J=7.6, 1.7 Hz, 1H),7.32-7.24 (m, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.95-6.87 (m, 1H), 5.61 (s,1H), 4.84 (d, J=3.7 Hz, 1H), 4.25-4.08 (m, 2H), 3.85-3.77 (m, 1H), 3.74(s, 3H), 3.30-3.13 (m, 1H), 2.56 (dd, J=3.8, 1.1 Hz, 1H), 1.67 (dd,J=10.9, 6.5 Hz, 1H), 1.56-1.45 (m, 1H), 1.47-1.34 (m, 3H), 1.33-1.22 (m,1H), 1.19 (t, J=7.1 Hz, 3H), 1.03 (s, 9H), 0.89-0.78 (m, 1H); MS (APCI+)m/z 432 (M+H)⁺.

Example 239D (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a cooled (ice bath) solution of (2S,3R,5S)-ethyl3-(tert-butyl)-5-(2-methoxyphenyl)-4-oxo-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 239C (0.426 g, 0.987 mmol) in ethanol (5 mL) was addedsodium borohydride (0.056 g, 1.481 mmol) in portions. The reaction wasstirred in the ice bath for 30 minutes and at ambient temperature for 60minutes. The solvent was removed and the crude material was quenchedwith saturated aqueous NH₄Cl (25 mL) and diluted with dichloromethane(100 mL). The organics were removed and washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude material waspurified using a 10 g silica gel cartridge, eluting with 5-100% methyltert-butyl ether/heptanes over 20 minutes to provide the title compound.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.80 (s, 1H), 7.19 (t, J=7.9 Hz, 1H),6.95 (d, J=8.1 Hz, 1H), 6.88 (t, J=7.5 Hz, 1H), 5.60 (s, 1H), 4.45 (s,1H), 4.38-4.30 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.75 (dq,J=11.5, 2.7, 1.5 Hz, 1H), 2.19 (t, J=3.5 Hz, 1H), 1.73-1.56 (m, 3H),1.55-1.40 (m, 2H), 1.42-1.27 (m, 4H), 1.22 (t, J=7.0 Hz, 3H), 0.97 (s,9H).

Example 239E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-4-hydroxy-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 239D (49 mg, 0.113 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (49 mg, 0.191 mmol) weredissolved in dry N,N-dimethylformamide (1 mL). After cooling in an icebath, a 1M solution of potassium 2-methylpropan-2-olate (0.181 mL, 0.181mmol) in tetrahydrofuran was added dropwise over 2 minutes. After 10minutes, the reaction was quenched with saturated aqueous NH₄Cl solution(1 mL) and extracted with dichloromethane (2×2 mL). The organic solventwas evaporated and the resulting crude material was loaded onto a 12 gsilica gel column and was eluted with 0-70% ethyl acetate/hexanes over20 minutes to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.89 (d, J=10.0 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.18 (s, 1H),6.96-6.84 (m, 3H), 5.77 (s, 1H), 4.61 (s, 1H), 4.24-4.22 (m, 1H),4.22-4.19 (m, 1H), 4.06 (qd, J=7.1, 1.6 Hz, 2H), 3.89 (d, J=13.0 Hz,1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.37-3.26 (m, 1H), 2.39 (t, J=2.4 Hz,1H), 2.29-2.16 (m, 2H), 2.02-1.86 (m, 6H), 1.89-1.77 (m, 2H), 1.72-1.60(m, 1H), 1.58-1.43 (m, 1H), 1.43-1.30 (m, 3H), 1.12 (t, J=7.1 Hz, 3H),0.98 (s, 9H); MS (APCI+) m/z 609 (M+H)⁺.

Example 239F(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 239E (46 mg, 0.076 mmol) in tetrahydrofuran (0.5 mL),methanol (0.500 mL) and water (0.500 mL) was added lithium hydroxidehydrate (22.20 mg, 0.529 mmol). The reaction was heated at 45° C. for 16hours. The solvent was removed under a stream of nitrogen. The crudematerial was acidified with 1M aqueous HCl (0.6 mL) and the resultingresidue was taken up in dichloromethane and purified using a 12 g silicagel cartridge with an ethyl acetate/ethanol/heptanes solvent system toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.22 (s,1H), 7.75 (d, J=2.6 Hz, 1H), 7.16 (s, 1H), 6.92-6.83 (m, 2H), 6.81 (d,J=2.3 Hz, 1H), 5.79 (s, 1H), 4.42 (s, 1H), 4.25 (d, J=13.2 Hz, 1H), 4.14(dd, J=6.9, 3.0 Hz, 1H), 3.96 (d, J=13.2 Hz, 1H), 3.86-3.72 (m, 8H),3.37-3.23 (m, 1H), 2.60 (t, J=3.2 Hz, 1H), 2.29-2.14 (m, 2H), 1.99-1.77(m, 5H), 1.72-1.58 (m, 1H), 1.58-1.43 (m, 1H), 1.44-1.28 (m, 2H), 1.25(s, 1H), 0.96 (s, 9H), 0.83 (d, J=6.7 Hz, 1H); MS (APCI+) m/z 581(M+H)⁺.

Example 240(2S,3R,4S,5S)-3-tert-butyl-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 240A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-4-hydroxy-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 239D (53 mg, 0.122 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (44 mg, 0.163mmol) were dissolved in dry N,N-dimethylformamide (1 mL). After coolingin an ice bath, a 1M solution of potassium 2-methylpropan-2-olate (0.196mL, 0.196 mmol) in tetrahydrofuran was added dropwise over 2 minutes.After 30 minutes, the mixture was quenched with saturated aqueous NH₄Clsolution and extracted with dichloromethane. The organic solvent wasevaporated and the crude material was loaded onto a 12 g silica gelcolumn eluting with 0-70% ethyl acetate/hexanes over 20 minutes toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (d,J=2.4 Hz, 1H), 7.85 (s, 1H), 7.17-7.10 (m, 2H), 6.88 (d, J=8.3 Hz, 1H),6.83 (d, J=7.7 Hz, 1H), 5.78 (s, 1H), 4.62 (s, 1H), 4.30 (d, J=13.7 Hz,1H), 4.25 (dd, J=6.1, 1.9 Hz, 1H), 4.07 (qq, J=7.2, 3.7 Hz, 2H), 3.92(d, J=13.8 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.74 (s, 1H), 2.39 (t,J=2.3 Hz, 1H), 1.73-1.60 (m, 2H), 1.60-1.42 (m, 1H), 1.44-1.27 (m, 5H),1.13 (t, J=7.1 Hz, 3H), 0.99 (s, 9H); MS (APCI+) m/z 623 (M+H)⁺.

Example 240B(2S,3R,4S,5S)-3-tert-butyl-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 240A (57 mg, 0.092 mmol) in tetrahydrofuran (0.5 mL),methanol (0.500 mL) and water (0.500 mL) was added lithium hydroxide,hydrate (26.9 mg, 0.641 mmol) and the reaction mixture was heated at 45°C. for 16 hours. The solvent was removed under a stream of nitrogen.Water (2 mL) was added to the crude material. The mixture was extractedwith 2×1 mL heptane (discarded). The desired product was extracted intodiethyl ether (3×1 mL), concentrated, and acidified with 1M aqueous HCl(0.5 mL) to pH˜2. The precipitate was purified using a 12 g silica gelcartridge with an ethyl acetate/ethanol/heptanes solvent system toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.35-8.25(m, 1H), 8.25 (s, 1H), 7.15-7.07 (m, 1H), 7.08-7.03 (m, 1H), 6.85-6.69(m, 2H), 5.99-5.60 (m, 1H), 4.45-4.37 (m, 1H), 4.34 (d, J=14.1 Hz, 1H),4.21-4.11 (m, 1H), 4.06-3.98 (m, 1H), 3.92-3.85 (m, 3H), 3.84-3.76 (m,1H), 3.73 (s, 3H), 2.65 (dd, J=10.8, 4.3 Hz, 2H), 1.73-1.60 (m, 1H),1.59-1.44 (m, 1H), 1.46-1.30 (m, 2H), 1.30-1.21 (m, 2H), 0.97 (s, 9H),0.83 (d, J=6.7 Hz, 1H); MS (APCI+) m/z 595 (M+H)⁺.

Example 241(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 241A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxypyridin-3-yl)methoxy)-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-4-hydroxy-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 239D (46 mg, 0.106 mmol) and3-(bromomethyl)-5-(tert-butyl)-2-methoxypyridine (52 mg, 0.201 mmol)were dissolved in dry N,N-dimethylformamide (1 mL). After cooling in anice bath, 1M potassium 2-methylpropan-2-olate (0.170 mL, 0.170 mmol)solution in tetrahydrofuran was added dropwise over 2 minutes. After 30minutes, the mixture was quenched with saturated aqueous NH₄Cl solutionand extracted with dichloromethane. The organic solvent was evaporatedand the residue was loaded onto a 12 g silica gel column eluting with0-70% ethyl acetate/hexanes over 20 minutes to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.98-7.79 (m, 1H), 7.24-7.02(m, 3H), 6.91 (d, J=8.1 Hz, 1H), 6.84 (t, J=7.4 Hz, 1H), 5.77 (s, 1H),4.59 (s, 1H), 4.24-4.17 (m, 2H), 4.05 (qd, J=7.1, 1.4 Hz, 2H), 3.87 (d,J=12.9 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.38 (t, J=2.4 Hz, 1H),1.73-1.57 (m, 2H), 1.57-1.43 (m, 2H), 1.36 (dt, J=10.9, 5.5 Hz, 5H),1.18 (s, 9H), 1.11 (t, J=7.1 Hz, 3H), 0.97 (s, 9H); MS (APCI+) m/z 611(M+H)⁺.

Example 241B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxypyridin-3-yl)methoxy)-5-(2-methoxyphenyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 241A (52 mg, 0.085 mmol) in tetrahydrofuran (0.5 mL),methanol (0.500 mL) and water (0.500 mL) was added lithium hydroxide H₂O(25.01 mg, 0.596 mmol). The reaction mixture was heated at 45° C. for 16hours. The solvent was removed under a stream of nitrogen. Water (2 mL)was added to the crude material. The mixture was extracted with 2×1 mLheptane (discarded). The desired product was extracted into diethylether (3×1 mL), and the organics were concentrated. Water (0.2 mL water)was added and the mixture was acidified with 1M aqueous HCl (0.3 mL) topH 2. The water was pipetted off and the precipitate was purified usinga 12 g silica gel cartridge with an ethyl acetate/ethanol/heptanessolvent system to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.99 (d, J=7.7 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 7.20-7.08 (m, 2H),6.90 (d, J=8.2 Hz, 1H), 6.83 (t, J=7.4 Hz, 1H), 5.74 (s, 1H), 4.52 (s,1H), 4.24-4.16 (m, 2H), 3.89 (d, J=13.0 Hz, 1H), 3.79 (s, 3H), 3.76 (s,3H), 3.64-3.40 (m, 1H), 3.18 (d, J=6.2 Hz, 1H), 1.72-1.60 (m, 2H),1.58-1.42 (m, 2H), 1.44-1.28 (m, 3H), 1.18 (s, 9H), 0.96 (s, 9H),0.85-0.77 (m, 1H); MS (APCI+) m/z 583 (M+H)⁺.

Example 242(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-6,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 242A (2-methoxy-6,8-dimethylquinolin-3-yl)methanol

To 2-methoxy-6,8-dimethylquinoline-3-carbaldehyde (500 mg, 2.323 mmol)in ethanol (5 mL) cooling in an ice bath, sodium borohydride (132 mg,3.48 mmol) was added in portions. The mixture was stirred in an ice bathfor 30 minutes. Saturated aqueous NH₄Cl (2 mL) was added and the solventwas removed under pressure. The residue was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic extractswas dried over sodium sulfate, filtered, and concentrated to provide thetitle compound, which was used in next step. MS (APCI+) m/z 218.2(M+H)⁺.

Example 242B 3-(bromomethyl)-2-methoxy-6,8-dimethylquinoline

The title compound was prepared according to the procedure described inExample 236A, substituting Example 242A for(2-chloro-5,7-dimethylquinolin-3-yl)methanol, to provide the titlecompound. MS (APCI+) m/z 280 (M+H)⁺.

Example 242C(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-6,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188 substituting Example 242B for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.08 (dd, J=7.2, 2.6 Hz, 1H), 7.26 (s, 1H), 7.18 (d,J=7.1 Hz, 2H), 7.13 (d, J=4.4 Hz, 3H), 5.56 (s, 1H), 4.66 (s, 1H),4.36-4.30 (m, 1H), 4.30-4.24 (m, 1H), 3.94 (dd, J=13.9, 1.3 Hz, 1H),3.91 (s, 3H), 3.77 (d, J=11.4 Hz, 1H), 3.39 (m, 2H), 2.54 (s, 3H),2.52-2.50 (m, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 1.70-1.30 (m, 6H), 1.02(s, 9H); MS (ESI+) m/z 589.3 (M+H)⁺.

Example 243(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 243A 2-methoxy-5-(prop-1-en-2-yl)pyridine

To a thick suspension of methyltriphenylphosphonium iodide (9.75 g, 24.0mmol) in anhydrous tetrahydrofuran (35 mL) under nitrogen and cooledwith a water ice bath, 1.0 M potassium tert-butoxide in tetrahydrofuran(23 mL, 23 mmol) was added slowly. The suspension was stirred cold forseventy minutes and treated over nearly ten minutes with a solution of1-(6-methoxypyridin-3-yl)ethanone (3.03 g, 20.0 mmol) in tetrahydrofuran(15 mL). After a couple of minutes, the bath was removed and thereaction mixture was stirred another 70 minutes before being quenchedwith acetone (2 mL). The mixture was stirred about three minutes andconcentrated. The residue was slurried with methyl tert-butyl ether (40mL) and filtered with a thorough methyl tert-butyl ether rinse (60 mL).The filtrate was concentrated and filtered through basic alumina with25% methyl tert-butyl ether/heptane, and the new filtrate wasconcentrated to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.27 (dd, J=2.6, 0.7 Hz, 1H), 7.86 (dd, J=8.7, 2.6 Hz, 1H), 6.79 (dd,J=8.7, 0.7 Hz, 1H), 5.39 (dq, J=1.5, 0.8 Hz, 1H), 5.05 (qd, J=1.5, 1.5Hz, 1H), 3.85 (s, 3H), 2.09 (dd, J=1.5, 0.8 Hz, 3H); MS (ESI) m/z 150(M+H)⁺.

Example 243B 2-methoxy-5-(1-methylcyclopropyl)pyridine

After 1.06 M solution of diethylzinc in heptane (11.3 mL, 12.0 mmol) wasadded to dichloromethane (25 mL) under nitrogen and cooled to 0° C., asolution of trifluoroacetic acid (920 μL, 12.0 mmol) in dichloromethane(15 mL) was added slowly. The resulting mixture was stirred twelveminutes, treated slowly with a solution of diiodomethane (960 μL, 11.9mmol) in dichloromethane (10 mL), stirred another twenty minutes andthen treated with a solution of 2-methoxy-5-(prop-1-en-2-yl)pyridine(597 mg, 4.00 mmol) in dichloromethane (10 mL). The reaction mixture wasallowed to slowly warm to room temperature over the weekend, quenched bythe addition of saturated aqueous NaHCO₃ (20 mL), and diluted withheptane (10 mL). The separated aqueous phase was extracted thrice withchloroform and the combined organic phases were dried with sodiumsulfate, filtered, concentrated and chromatographed on basic alumina (20to 50% CHCl₃/heptane) to provide the title compound. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.08 (d, J=2.5 Hz, 1H), 7.45 (dd, J=8.6, 2.5 Hz, 1H), 6.66(d, J=8.6 Hz, 1H), 3.91 (s, 3H), 1.37 (s, 3H), 0.81-0.77 (m, 2H),0.72-0.68 (m, 2H); MS (ESI) m/z 164 (M+H)⁺.

Example 243C 2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl)methanol

To a solution of TMEDA (tetramethylethylenediamine, 132 μL, 0.88 mmol)in anhydrous methyl tert-butyl ether (2.0 mL) under nitrogen and cooledto 0° C. was added 2.05 M n-butyllithium in cyclohexane (410 μL, 0.84mmol). After a couple of minutes, a dropwise solution of impure2-methoxy-5-(1-methylcyclopropyl)pyridine (98 mg, <0.6 mmol) in methyltert-butyl ether (1.5 mL) was added. After a few minutes, the mixturewas removed from the bath and stirred at room temperature more thantwenty minutes before being cannulated dropwise into a suspension ofparaformaldehyde (30 mg, 1.0 mmol) in methyl tert-butyl ether (2.0 mL)under nitrogen. The mixture was cooled with a water ice bath, with amethyl tert-butyl ether (0.5 mL) rinse. After six hours, the reactionmixture was quenched with 3 M aqueous citric acid (400 μL) and dilutedwith brine (400 μL). The aqueous phase was separated and extracted withmethyl tert-butyl ether and the combined organic phases were dried(Na₂SO₄), filtered, and concentrated. The residue was chromatographed onsilica (20 to 30% methyl tert-butyl ether/heptane) to provide the titlecompound. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.00 (d, J=2.4 Hz, 1H),7.47-7.46 (m, 1H), 4.63 (d, J=5.6 Hz, 2H), 3.97 (s, 3H), 2.36-2.31 (m,1H), 1.37 (s, 3H), 0.81-0.78 (m, 2H), 0.72-0.69 (m, 2H); MS (ESI) m/z194 (M+H)⁺.

Example 243D 3-(bromomethyl)-2-methoxy-5-(1-methylcyclopropyl)pyridine

To a solution of Example 243C (60 mg, 0.31 mmol) and triphenylphosphine(97 mg, 0.37 mmol) in anhydrous dichloromethane (1.0 mL) under nitrogenand cooled with a water ice bath was added dropwise a solution oftetrabromomethane (123 mg, 0.37 mmol) in dichloromethane (0.5 mL). Afterthe reaction solution had been stirred a minute, the bath was removedand the mixture was stirred at room temperature about 45 minutes beforebeing concentrated and chromatographed on silica (20 to 40%CHCl₃/heptane) to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δppm 8.03 (d, J=2.4 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 4.47 (s, 2H), 3.99(s, 3H), 1.37 (s, 3H), 0.82-0.76 (m, 2H), 0.75-0.70 (m, 2H); MS (ESI)m/z 256, 258 (M+H)⁺.

Example 243E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

Example 170B (74 mg, 0.17 mmol) was dissolved into anhydrous toluene,dried twice over NaSO₄, filtered, and concentrated. The residue wasplaced under nitrogen, dissolved into anhydrous N,N-dimethylformamide(350 μL), cooled to −40° C., treated first with a solution of Example243D (51 mg, 0.20 mmol) in N,N-dimethylformamide (250 μL) and thendropwise over several minutes with 1 M potassium tert-butoxide intetrahydrofuran (190 μL, 0.19 mmol). The reaction mixture was permittedto warm slowly over almost two hours to nearly room temperature beforeit was quenched with 3 M aqueous citric acid (70 μL). Brine was addedand the reaction mixture was extracted thrice with methyl tert-butylether. The combined organic phases were dried (Na₂SO₄), filtered,concentrated and chromatographed on silica (20 to 30% methyl tert-butylether/heptane) to give the crude title compound which was used in thenext step without further purification. MS (ESI+) m/z 593 (M+H)⁺.

Example 243F(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 243E (80 mg) was dissolved into tetrahydrofuran (900 μL) andmethanol (400 μL), treated with 1.5 M aqueous LiOH (900 μL) and heatedat 50° C. overnight. The reaction mixture was brought to roomtemperature and was quenched with 3 M aqueous citric acid (250 μL),diluted with brine (500 μL) and extracted thrice with methyl tert-butylether. The combined organic phases were dried (Na₂SO₄), filtered,concentrated and chromatographed on silica (10 to 70% methyl tert-butylether in 1:3 CH₂Cl₂/heptane) to give the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 7.83 (d, J=2.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.24-7.12(m, 3H), 6.77-6.74 (m, 1H), 5.80 (d, J=5.6 Hz, 1H), 4.82-4.79 (m, 1H),4.38 (d, J=13.8 Hz, 1H), 4.16 (d, J=5.6 Hz, 1H), 3.92 (d, J=13.8 Hz,1H), 3.87-3.81 (m, 1H), 3.80 (s, 3H), 3.32-3.27 (m, 1H), 2.92-2.89 (m,1H), 2.86-2.78 (m, 1H), 2.32 (s, 3H), 1.78-1.70 (m, 1H), 1.68-1.42 (m,3H), 1.36-1.25 (m, 3H), 1.24 (s, 3H), 1.06 (s, 9H), 0.65-0.59 (m, 4H);MS (ESI+) m/z 565 (M+H)⁺.

Example 244(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-8-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 244A 3-(bromomethyl)-2-methoxy-8-methylquinoline

The title compound was prepared according to the procedure described inExample 236A, substituting (2-methoxy-8-methylquinolin-3-yl)methanol for(2-chloro-5,7-dimethylquinolin-3-yl)methanol. MS (APCI+) m/z 266 (M+H)⁺.

Example 244B(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-8-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 188 substituting Example 244A for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.08 (dd, J=6.8, 2.4 Hz, 1H), 7.51-7.37 (m, 2H),7.36-7.20 (m, 2H), 7.13 (d, J=4.9 Hz, 3H), 5.57 (s, 1H), 4.67 (s, 1H),4.34 (dd, J=13.9, 1.2 Hz, 1H), 4.29 (d, J=5.9 Hz, 1H), 4.02-3.95 (m,1H), 3.93 (s, 3H), 3.77 (d, J=11.6 Hz, 1H), 3.39 (m, 2H), 2.58 (s, 3H),2.53 (d, J=1.8 Hz, 1H), 2.31 (s, 3H), 1.70-1.29 (m, 6H), 1.02 (s, 9H);MS (ESI+): m/e 575.2 (M+H)⁺.

Example 245(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 245A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate(Example 169A, 10 g, 28.5 mmol) in dichloromethane (143 mL) was addedtriethylamine (7.95 mL, 57.1 mmol). The solution was cooled in an icebath to 5° C., isopropyl carbonochloridate (15.69 mL, 31.4 mmol) wasadded as a solution in toluene slowly and an exotherm to ˜15° C. wasnoted. A solid formed, so the vial was removed from the bath and stirredat room temperature. The reaction was complete as soon as thechloroformate was added. The mixture was diluted with methyl tert-butylether and saturated aqueous sodium bicarbonate was added. The mixturewas allowed to stir overnight at room temperature. The organics waswashed with brine, dried over MgSO₄, filtered, and concentrated toprovide the title compound. MS (ESI+) m/z 437 (M+H)⁺.

Example 245B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

To Example 245A (80 mg, 0.183 mmol) and2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (Intermediate 6, 47.1mg, 0.183 mmol) in N,N-dimethylformamide (2 mL) cooling in an ice bath,was added dropwise potassium 2-methylpropan-2-olate (30.8 mg, 0.275mmol, 0.28 mL, 1.0M in tetrahydrofuran). The mixture was stirred in anice bath for 20 minutes, and allowed to stir at ambient temperature for30 minutes. The solvent was concentrated and methanol (2 mL) and 6Maqueous LiOH (0.5 mL) were added. The mixture was stirred at 50° C. for5 hours, and saturated aqueous NH₄Cl (2 mL) and dichloromethane (20 mL)were added. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified via chromatographyon a 12 g silica gel cartridge, eluting with ethyl acetate/methanol(9:1) in heptane, at a 0-60% gradient to provide the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.11 (ddd, J=7.4, 2.0, 0.7 Hz, 1H), 7.91(dd, J=4.9, 2.0 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.82 (d, J=2.7Hz, 1H), 6.78 (dd, J=7.4, 5.0 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.26 (p,J=6.1 Hz, 1H), 5.16 (d, J=6.0 Hz, 1H), 4.65 (dq, J=12.4, 6.2 Hz, 1H),4.34 (d, J=2.6 Hz, 1H), 4.27 (d, J=12.4 Hz, 1H), 4.19 (dd, J=6.0, 1.7Hz, 1H), 3.95 (d, J=12.4 Hz, 1H), 3.62 (s, 3H), 1.30 (d, J=6.1 Hz, 3H),1.25 (d, J=6.2 Hz, 3H), 1.16 (s, 9H), 1.05 (d, J=6.2 Hz, 3H), 0.96 (s,9H), 0.91 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 585 (M+H)⁺.

Example 246(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 246A 2-methoxy-5-(1-methylcyclobutyl)benzaldehyde

1-Methoxy-4-(1-methylcyclobutyl)benzene (3 g, 17.02 mmol) was dissolvedin 110 mL of dichloromethane, and the solution was cooled to <0° C. inan ice brine bath. After addition of dichloro(methoxy)methane (1.693 mL,18.72 mmol), titanium tetrachloride (2.065 mL, 18.72 mmol) was addeddropwise as a solution in 10 mL of dichloromethane over 2 minutes,maintaining an internal temperature<5° C. After 15 minutes at the sametemperature, TLC indicated complete conversion. Water (40 mL) was addedto quench (exotherm to ˜15° C.) the reaction, and the organic layer wasconcentrated and loaded onto an 80 g silica gel column, eluting with0-15% ethyl acetate/heptane over 20 minutes to provide the titlecompound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 10.49 (d, J=1.0 Hz, 1H),7.67 (dd, J=2.6, 0.9 Hz, 1H), 7.40 (ddd, J=8.6, 2.5, 1.0 Hz, 1H), 6.96(d, J=8.6 Hz, 1H), 3.94 (d, J=1.0 Hz, 3H), 2.37 (td, J=10.4, 9.7, 7.3Hz, 2H), 2.18-2.04 (m, 3H), 1.89-1.81 (m, 1H), 1.46 (s, 3H); MS (ESI+)m/z 205 (M+H)⁺.

Example 246B (2-methoxy-5-(1-methylcyclobutyl)phenyl) methanol

To Example 246A (1.0 g, 4.9 mmol) in ethanol (20 mL) cooled in an icebath, sodium borohydride (0.204 g, 5.39 mmol) was added in portions. Themixture was stirred in an ice bath for 30 minutes. Saturated aqueousNH₄Cl (2 mL) was added and solvent was removed under reduced pressure,and the residue was partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate. The organics were washed with brine, driedover sodium sulfate, filtered, and concentrated to provide the titlecompound. MS (APCI+) m/z 189 (M-OH)⁺.

Example 246C 2-(bromomethyl)-1-methoxy-4-(1-methylcyclobutyl)benzene

To triphenylphosphine (2365 mg, 9.02 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (1605 mg,9.02 mmol) portionwise. The mixture was stirred for 30 minutesmaintaining an internal temperature<10° C., and(2-methoxy-5-(1-methylcyclobutyl)phenyl)methanol (930 mg, 4.51 mmol) indichloromethane (2 mL) was added slowly at <10° C. The mixture wasstirred in ice bath for 1 hour. Saturated aqueous NH₄Cl (2 mL) was addedand the mixture was concentrated. The residue was partitioned betweenethyl acetate and saturated aqueous sodium bicarbonate. The organicextracts were dried over sodium sulfate, filtered, and concentrated toprovide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm7.17-7.11 (m, 2H), 6.84 (s, 1H), 4.60 (s, 2H), 3.91 (s, 3H), 2.40-2.30(m, 2H), 2.16-1.98 (m, 3H), 1.87-1.77 (m, 1H), 1.46 (d, J=0.7 Hz, 3H).

Example 246D(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 245B, substituting Example 246C for Intermediate 6 to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.09 (dd, J=7.3, 1.9Hz, 1H), 7.91 (dd, J=4.9, 2.0 Hz, 1H), 6.93 (dd, J=8.4, 2.5 Hz, 1H),6.78 (dd, J=7.4, 4.9 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.61 (d, J=2.5 Hz,1H), 5.30-5.22 (m, 1H), 5.16 (d, J=6.0 Hz, 1H), 4.66 (h, J=6.2 Hz, 1H),4.34 (d, J=2.5 Hz, 1H), 4.27 (d, J=12.4 Hz, 1H), 4.19 (dd, J=6.0, 1.7Hz, 1H), 3.94 (d, J=12.5 Hz, 1H), 3.62 (s, 3H), 2.45 (m, 1H), 2.22-2.12(m, 2H), 2.04-1.91 (m, 3H), 1.78-1.69 (m, 1H), 1.29 (t, J=3.1 Hz, 6H),1.24 (d, J=6.2 Hz, 3H), 1.04 (d, J=6.2 Hz, 3H), 0.96 (s, 9H), 0.91 (d,J=6.2 Hz, 3H); MS (ESI+) m/z 597 (M+H)⁺.

Example 247(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 247A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydrofuran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

A solution of Example 170A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(o-tolyl)pyrrolidine-2-carboxylate) (1.094 g,3.58 mmol) in CH₂Cl₂ (20 mL) under N₂ was cooled to 0° C., treated withtriethylamine (0.999 mL, 7.17 mmol), treated dropwise with a solution of(S)-tetrahydrofuran-2-carbonyl chloride (0.579 g, 4.3 mmol) in CH₂Cl₂(˜5 mL) over 5 minutes, stirred at 0° C. for 20 minutes, treated withsaturated aqueous NH₄Cl solution (15 mL) and the layers were separated.The aqueous layer was diluted with water (10 mL) and extracted withCH₂Cl₂ (2×25 mL). The combined CH₂Cl₂ layers were dried (MgSO₄),filtered, concentrated and chromatographed on silica gel, eluting with agradient of 15% to 100% ethyl acetate in heptane to provide the titlecompound. LC/MS (ESI+) m/z 404 (M+H)⁺.

Example 247B(2S,3R,4S,5S)-3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydrofuran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylicacid

A solution of Example 247A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydrofuran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(208.5 mg, 0.517 mmol) in tetrahydrofuran (1 mL) was diluted withmethanol (1 mL), treated with 1 M aqueous NaOH (1 mL) and stirred atroom temperature for 30 minutes. The mixture was treated with methyltert-butyl ether (5 mL), treated with 1 M aqueous HCl (3 mL) andextracted with methyl tert-butyl ether (2×30 mL). The combined organiclayers were washed with brine, dried (MgSO₄), filtered, and concentratedto provide the title compound. LC/MS (ESI+) m/z 376 (M+H)⁺.

Example 247C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 247B((2S,3R,4S,5S)-3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydrofuran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylicacid) (67.5 mg, 0.180 mmol) in N,N-dimethylformamide (1 mL) under N₂ wascooled to 0° C., treated with 1 M potassium tert-butoxide intetrahydrofuran (539 μL, 0.539 mmol), stirred at room temperature for 15minutes, cooled to −30° C., treated with a solution of Intermediate 6(2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene) (50.9 mg, 0.198 mmol)in tetrahydrofuran (0.5 mL), stirred at −30° C. for 15 minutes, dilutedwith methyl tert-butyl ether (10 mL) and quenched with 1 M aqueous HCl(2 mL). The mixture was partitioned between methyl tert-butyl ether (40mL) and water (10 mL). The layers were separated and the aqueous layerwas extracted with methyl tert-butyl ether (30 mL). The combined methyltert-butyl ether layers were washed with brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel, eluting with a gradientof 10% to 50% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptane to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.99-7.90(m, 1H), 7.14 (dd, J=2.7, 8.6 Hz, 1H), 7.11-7.07 (m, 3H), 6.85 (d, J=2.6Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.27 (d, J=6.0 Hz, 1H), 4.62 (d, J=2.3Hz, 1H), 4.27 (d, J=6.0 Hz, 1H), 4.19 (d, J=12.4 Hz, 1H), 3.88-3.80 (m,2H), 3.65 (s, 4H), 3.60-3.51 (m, 2H), 3.00-2.75 (m, 1H), 2.62-2.56 (m,1H), 2.37 (s, 3H), 1.90-1.80 (m, 1H), 1.63-1.42 (m, 1H), 1.20 (s, 9H),1.01 (s, 9H); LC/MS (ESI+) m/z 552 (M+H)⁺.

Example 248(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 245B, substituting Example 169B for Example 245A, and Example237C for Intermediate 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.91 (d, J=5.0Hz, 1H), 7.62 (s, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H),6.82 (s, 1H), 5.36 (s, 1H), 5.22 (p, J=6.1 Hz, 1H), 4.56 (d, J=2.8 Hz,1H), 4.46 (d, J=13.4 Hz, 1H), 4.33 (dd, J=6.2, 2.1 Hz, 1H), 4.14 (d,J=13.4 Hz, 1H), 3.93 (s, 3H), 2.57 (s, 1H), 2.53 (s, 3H), 2.42 (s, 3H),2.28 (s, 1H), 1.68 (s, 2H), 1.30 (d, J=6.1 Hz, 3H), 1.25 (s, 2H), 1.19(d, J=6.1 Hz, 3H), 1.12 (d, J=29.0 Hz, 3H), 1.02 (s, 9H); MS (ESI+) m/z632 (M+H)⁺.

Example 249(2S,3R,4S,5S)-3-tert-butyl-4-({2-[2-methoxy-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 249A 1-(2-methoxy-5-(trifluoromethyl)phenyl)ethan-1-one

A 250 mL 3-neck round bottom flask equipped with a thermometer and anaddition funnel was charged with trifluoromethanesulfonic acid (29.6 mL,333 mmol) and then treated dropwise (˜6 drops/minute) under N₂ over 3hours with a mixture of 4-(trifluoromethyl)anisole (11.74 g, 66.6 mmol)and acetic anhydride (12.57 mL, 133 mmol) keeping the internaltemperature at or below 30° C. The resulting mixture was stirred at roomtemperature for 3 hours and then poured carefully into 150 mL of icewater, adding more ice during the addition to prevent the mixture fromwarming. The mixture was extracted with methyl tert-butyl ether (twice,150 mL and 50 mL). The combined methyl tert-butyl ether layers werewashed with saturated aqueous NaHCO₃ solution 4 times (100 mL, 100 mL,50 mL and 50 mL). The methyl tert-butyl ether layer was washed withbrine, dried (MgSO₄), filtered, concentrated, and chromatographed onsilica gel, eluting with a gradient of 5% to 10% ethyl acetate inheptane to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm8.00 (dd, J=0.8, 2.5 Hz, 1H), 7.70 (ddd, J=0.8, 2.5, 8.8 Hz, 1H), 7.05(d, J=8.7 Hz, 1H), 3.97 (s, 3H), 2.62 (s, 3H).

Example 249B 1-methoxy-2-(prop-1-en-2-yl)-4-(trifluoromethyl)benzene

A suspension of methyltriphenoxyphosphonium iodide (1.443 g, 3.19 mmol)in tetrahydrofuran (5 mL) at 0° C. under N₂ was treated dropwise with 1M potassium tert-butoxide in tetrahydrofuran (3.06 mL, 3.06 mmol),stirred at 0° C. for 2 hours, treated with a solution of Example 249A(1-(2-methoxy-5-(trifluoromethyl)phenyl)ethanone) (0.58 g, 2.66 mmol) intetrahydrofuran (3 mL) and stirred at room temperature for 1 hour. Themixture was diluted with methyl tert-butyl ether (50 mL) and washed withwater (20 mL). The layers were separated and the aqueous layer wasextracted with methyl tert-butyl ether (30 mL). The combined methyltert-butyl ether layers were washed with brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel, eluting with 10% ethylacetate in heptane to provide the title compound. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.53-7.49 (m, 1H), 7.44 (d, J=2.5 Hz, 1H), 6.93 (d, J=8.5Hz, 1H), 5.22-5.20 (m, 1H), 5.10 (dd, J=0.9, 2.0 Hz, 1H), 3.89 (s, 3H),2.12 (dd, J=0.9, 1.5 Hz, 3H).

Example 249C2-(3-bromoprop-1-en-2-yl)-1-methoxy-4-(trifluoromethyl)benzene

A solution of Example 249B(1-methoxy-2-(prop-1-en-2-yl)-4-(trifluoromethyl)benzene) (233 mg, 1.078mmol) in tetrahydrofuran (3 mL) was treated with N-bromosuccinimide (201mg, 1.132 mmol), treated with p-toluenesulfonic acid monohydrate (20.50mg, 0.108 mmol), stirred at reflux under N₂ for 2 hours, cooled, anddiluted with heptanes (30 mL). A solid formed. The solid was removed byfiltration and discarded. The filtrate was washed with 50% saturatedaqueous NaHCO₃ solution (˜10 mL), washed with water (2×20 mL), washedwith brine, dried (MgSO₄), filtered, and concentrated. The residue wastreated with heptanes (3 mL) and a second solid formed. The heptanesolution was decanted away from this solid, and the second solid wasdecanted with more heptanes. The second solid was discarded. Thecombined heptane decantations were concentrated and chromatographed onsilica gel, eluting first with heptanes, and then eluting with 10%methyl tert-butyl ether in heptanes to provide the title compound. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.58 (dd, J=2.3, 8.7 Hz, 1H), 7.48 (d, J=2.3Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 5.56 (d, J=1.1 Hz, 1H), 5.28 (d, J=1.0Hz, 1H), 4.43 (d, J=0.8 Hz, 2H), 3.89 (s, 3H).

Example 249D ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)allyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

A flask containing Example 249C(2-(3-bromoprop-1-en-2-yl)-1-methoxy-4-(trifluoromethyl)benzene) (81 mg,0.274 mmol) was treated with Example 170B ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(88 mg, 0.211 mmol), treated with toluene (˜2 mL) and the solution wasconcentrated. The residue was dissolved in N,N-dimethylformamide (1 mL)under N₂, cooled to −30° C., treated with 1 M potassium tert-butoxide intetrahydrofuran (253 μL, 0.253 mmol), stirred at −30° C. for 15 minutes,quenched with saturated aqueous NH₄Cl solution (1 mL) and partitionedbetween water (15 mL) and methyl tert-butyl ether (50 mL). The layerswere separated and the aqueous layer was extracted with methyltert-butyl ether (30 mL). The combined methyl tert-butyl ether layerswere washed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 15% to 100%ethyl acetate in heptanes to provide the title compound. LC/MS (ESI+)m/z 632 (M+H)⁺.

Example 249E(2S,3R,4S,5S)-3-tert-butyl-4-({2-[2-methoxy-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 249D ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)allyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(11 mg, 0.017 mmol) in tetrahydrofuran (0.2), was diluted with methanol(0.1 mL) and water (0.2 mL), treated with lithium hydroxide monohydrate(7.31 mg, 0.174 mmol), stirred at 55° C. for 1 hour, treated with morelithium hydroxide monohydrate (˜10 mg), heated to 55° C. overnight,heated to 60° C. for an additional 4 hours, cooled, treated with 1 Maqueous HCl (2 mL) and extracted with ethyl acetate (30 mL). The ethylacetate layer was washed with brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel, eluting with a gradientof 15% to 100% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptane to providethe title compound. ¹H NMR (400 MHz, DMSO, 120° C.) δ ppm 7.97 (dd,J=2.5, 7.5 Hz, 1H), 7.56-7.51 (m, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.14-7.03(m, 4H), 5.48 (s, 1H), 4.99-4.95 (m, 2H), 4.62-4.59 (m, 1H), 4.14 (d,J=5.8 Hz, 1H), 3.87-3.83 (m, 1H), 3.81-3.76 (m, 1H), 3.75 (s, 3H), 3.60(dt, J=1.4, 13.5 Hz, 1H), 2.42-2.40 (m, 1H), 2.32 (s, 3H), 1.72-1.63 (m,1H), 1.53 (d, J=12.0 Hz, 1H), 1.46-1.25 (m, 4H), 0.99 (s, 9H), 0.93-0.82(m, 2H); LC/MS (ESI+) m/z 604 (M+H)⁺.

Example 250(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 245B, substituting Example 169B for Example 245A, andIntermediate 10 for Intermediate 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.19(s, 1H), 8.03-7.89 (m, 2H), 6.81 (s, 1H), 5.35 (s, 1H), 5.29 (p, J=6.1Hz, 1H), 4.54-4.51 (m, 1H), 4.30 (s, 1H), 4.26 (dd, J=5.7, 3.5 Hz, 1H),3.97 (d, J=13.0 Hz, 1H), 3.76 (s, 3H), 2.50 (s, 1H), 2.12 (s, 1H), 1.60(d, J=64.8 Hz, 4H), 1.33 (s, 2H), 1.29 (d, J=15.3 Hz, 4H), 1.26 (s, 3H),1.18 (s, 7H), 1.11 (s, 2H), 0.98 (s, 9H); MS (ESI+) m/z 610.3 (M+H)⁺.

Example 251(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 245B, substituting Example 169B for Example 245A. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.32-8.03 (m, 1H), 7.95 (s, 1H), 7.12-7.06 (m, 1H),6.83-6.76 (m, 2H), 6.73 (d, J=8.6 Hz, 1H), 5.31 (td, J=12.3, 6.0 Hz,2H), 4.48 (d, J=3.0 Hz, 1H), 4.28 (d, J=12.3 Hz, 1H), 4.21 (dd, J=6.3,2.4 Hz, 1H), 3.98 (d, J=12.3 Hz, 1H), 3.63 (s, 3H), 1.67 (s, 3H), 1.51(s, 3H), 1.32 (d, J=6.1 Hz, 3H), 1.27 (d, J=4.8 Hz, 3H), 1.26 (s, 1H),1.24 (t, J=2.2 Hz, 1H), 1.16 (s, 9H), 1.14-1.02 (m, 3H), 0.96 (s, 9H);MS (ESI+) m/z 609 (M+H)⁺.

Example 252(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 245B, substituting Example 169B for Example 245A, and Example238A for Intermediate 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (s, 1H),7.92 (s, 1H), 7.56 (s, 1H), 7.32 (s, 1H), 7.02 (s, 1H), 6.82 (s, 1H),5.37 (s, 1H), 5.23 (p, J=6.1 Hz, 1H), 4.55 (d, J=2.8 Hz, 1H), 4.43 (dd,J=13.4, 1.2 Hz, 1H), 4.33 (dd, J=6.2, 2.1 Hz, 1H), 4.11 (d, J=13.5 Hz,1H), 3.89 (s, 3H), 2.56 (s, 1H), 2.53 (s, 1H), 2.43 (s, 3H), 2.38 (s,3H), 1.67 (s, 3H), 1.52 (s, 3H), 1.37 (d, J=16.9 Hz, 1H), 1.30 (d, J=6.1Hz, 3H), 1.25 (d, J=3.8 Hz, 1H), 1.20 (d, J=6.2 Hz, 3H), 1.07 (s, 2H),1.01 (s, 9H); MS (ESI+) m/z 632 (M+H)⁺.

Example 253(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 245B, substituting Example 238A for Intermediate 6. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.14 (d, J=42.2 Hz, 1H), 7.91-7.86 (m, 1H), 7.45 (d,J=23.7 Hz, 1H), 7.32 (s, 1H), 7.02 (s, 1H), 6.88 (dd, J=7.4, 4.9 Hz,1H), 5.10 (d, J=9.9 Hz, 2H), 4.65 (d, J=43.4 Hz, 2H), 4.44 (d, J=14.0Hz, 1H), 4.38-4.28 (m, 2H), 4.08 (d, J=14.0 Hz, 1H), 3.84 (s, 3H), 2.37(s, 3H), 2.35 (s, 3H), 1.23 (d, J=6.0 Hz, 3H), 1.19-1.10 (m, 3H), 1.07(s, 3H), 0.98 (s, 9H), 0.85-0.57 (m, 3H); MS (ESI+) m/z 608 (M+H)⁺.

Example 254(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 254A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 278C (184 mg, 0.426 mmol) and3-(bromomethyl)-2-methoxyquinoline (140 mg, 0.554 mmol) were dissolvedin dry N,N-dimethylformamide (2.2 mL). After cooling in an ice bath,potassium 2-methylpropan-2-olate (0.597 mL, 0.597 mmol) 1 M solution intetrahydrofuran was added dropwise over 2 minutes. After 30 minutes, themixture was quenched with saturated aqueous NH₄Cl solution and extractedwith dichloromethane. The organic solvent was evaporated and the cruderesidue was loaded onto a 24 g silica gel column eluting with 0-70%ethyl acetate/heptanes over 20 minutes to provide the title compound. ¹HNMR (501 MHz, DMSO-d₆) δ ppm 8.15-8.07 (m, 1H), 7.68 (d, J=8.6 Hz, 1H),7.60-7.54 (m, 1H), 7.52-7.48 (m, 1H), 7.42-7.36 (m, 1H), 7.32 (dd,J=7.4, 1.6 Hz, 1H), 7.27 (tt, J=7.7, 3.5 Hz, 1H), 7.19-7.09 (m, 1H),7.04 (d, J=8.6 Hz, 1H), 5.67 (d, J=5.5 Hz, 1H), 4.66 (dd, J=15.2, 1.6Hz, 1H), 4.37 (dd, J=14.3, 1.6 Hz, 1H), 4.28 (dd, J=14.5, 5.7 Hz, 1H),4.09 (q, J=7.0 Hz, 1H), 3.98 (dd, J=14.4, 1.4 Hz, 1H), 3.88 (s, 2H),3.73 (d, J=11.2 Hz, 1H), 3.23 (dd, J=10.5, 2.5 Hz, 2H), 2.79-2.67 (m,1H), 2.66-2.53 (m, 1H), 1.64 (dd, J=28.9, 13.0 Hz, 1H), 1.51 (d, J=9.7Hz, 1H), 1.43 (q, J=10.0 Hz, 1H), 1.33-1.21 (m, 3H), 1.12 (dt, J=13.9,7.3 Hz, 6H), 1.01 (d, J=1.7 Hz, 9H); MS (APCI+) m/z 604 (M+H)⁺.

Example 254B(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((2-methoxyquinolin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 254A (145 mg, 0.241 mmol) in tetrahydrofuran (0.7 mL),methanol (0.700 mL) and water (0.700 mL) was added lithium hydroxidehydrate (70.7 mg, 1.684 mmol) and the reaction was heated at 45° C. for16 hours. The solvent was removed under a stream of nitrogen. Water (2mL) was added to the crude material, and the mixture was extracted with5 mL heptane (discarded). The product was extracted into diethyl ether.The mixture was concentrated and 1 mL water was added. The mixture wasacidified with 1M aqueous HCl (0.2 mL) to pH˜6, and the precipitate wasfiltered to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.20 (dd, J=7.8, 1.4 Hz, 1H), 7.67 (dt, J=8.8, 0.9 Hz, 1H), 7.54 (ddd,J=7.2, 3.9, 2.2 Hz, 2H), 7.34 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 7.23 (s,1H), 7.22-7.09 (m, 3H), 5.58 (s, 1H), 4.63 (s, 1H), 4.35 (dd, J=14.2,1.3 Hz, 1H), 4.24 (d, J=5.8 Hz, 1H), 3.96 (dd, J=14.1, 1.3 Hz, 1H), 3.92(s, 3H), 3.76 (d, J=11.2 Hz, 1H), 2.80-2.62 (m, 2H), 2.59 (s, 1H), 1.68(d, J=12.6 Hz, 1H), 1.55 (m, 2H), 1.36 (m, 3H), 1.19 (t, J=7.5 Hz, 3H),1.03 (s, 9H); MS (APCI+) m/z 575 (M+H)⁺.

Example 255(2S,3R,4S,5S)-3-tert-butyl-4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-5-(2-methyl-phenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 255A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

Example 170B (74 mg, 0.17 mmol) was dissolved into anhydrous toluene,dried twice over NaSO₄, filtered, and concentrated. The residue wasplaced under nitrogen, dissolved into anhydrous N,N-dimethylformamide(500 μL), cooled to near −35° C., treated first with a suspension of2-(bromomethyl)-1-methyl-1H-benzo[d]imidazole (45 mg, 0.20 mmol) inN,N-dimethylformamide (1.0 mL) and then dropwise with 1 M potassiumtert-butoxide in tetrahydrofuran (190 μL, 0.19 mmol). The reactionmixture was permitted to warm to 10° C. over an hour, removed from thebath and stirred five more minutes before it was quenched with 3 Maqueous citric acid (40 μL). The mixture was concentrated and purifiedby reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm,flow rate 40 mL/minute, 5-60% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid] to give the title compound. MS (ESI+) m/z 562(M+H)⁺.

Example 255B(2S,3R,4S,5S)-3-tert-butyl-4-[(1-1H-benzimidazol-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 255A (18 mg, 32 mol) was dissolved into tetrahydrofuran (200 μL)and methanol (100 μL), treated with 1.5 M aqueous LiOH (150 μL) andstirred at room temperature four days. The reaction mixture wasconcentrated and placed directly onto silica for chromatography (1% [88%aqueous HCOOH] and 0 to 20% CH₃CN in methyl tert-butyl ether) to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.01-7.96(m, 1H), 7.60-7.56 (m, 1H), 7.43-7.39 (m, 1H), 7.30-7.25 (m, 1H),7.25-7.20 (m, 1H), 7.13-7.06 (m, 2H), 7.03-6.97 (m, 1H), 5.48 (m, 1H),4.66-4.62 (m, 1H), 4.42 (d, J=13.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 1H), 4.24(d, J=13.0 Hz, 1H), 3.76-3.69 (m, 1H), 3.1-3.0 (m, 2H), 2.46-2.44 (m,1H), 2.11 (s, 3H), 1.69-1.60 (m, 1H), 1.58-1.44 (m, 1H), 1.43-1.24 (m,3H), 1.02-0.95 (m, 1H), 0.99 (s, 9H); MS (ESI+) m/z 534 (M+H)⁺.

Example 256(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)pyrrolidine-2-carboxylicacid Example 256A (E)-ethyl2-(((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methylene)amino)acetate

Ethyl 2-aminoacetate hydrochloride (4.95 g, 35.5 mmol) and magnesiumsulfate (6.83 g, 56.7 mmol) were suspended in dichloromethane (47.3 mL)and the suspension was treated with triethylamine (4.94 mL, 35.5 mmol).The mixture was stirred at room temperature for 1 hour, and2,2-dimethyl-2,3-dihydrobenzofuran-7-carbaldehyde (5 g, 28.4 mmol) wasadded. The mixture was stirred at room temperature for 20 hours. Thesolid material was removed via filtration and the filtrate was washedwith water (quick wash twice) and brine, dried over sodium sulfate,filtered, and concentrated to provide the title compound. ¹H NMR (400MHz, Chloroform-d) δ ppm 8.53 (d, J=1.5 Hz, 1H), 7.78 (dd, J=8.0, 1.2Hz, 1H), 7.19 (dq, J=7.2, 1.3 Hz, 1H), 6.84 (t, J=7.4 Hz, 1H), 4.39 (d,J=1.3 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.01 (t, J=1.1 Hz, 2H), 1.50 (s,6H), 1.30 (t, J=7.1 Hz, 3H); MS (DCI+) m/z 262.0 (M+H)⁺.

Example 256B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.278 g, 0.369 mmol) and copper (I) triflate dimer, benzene complex(0.071 g, 0.142 mmol) were dissolved in tetrahydrofuran (72.7 mL) thathad been sparged with an N₂ stream for 4 hours. The resulting solutionwas stirred for 1.5 hours at room temperature, and (E)-ethyl2-(((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methylene)amino)acetate(7.41 g, 28.4 mmol) in tetrahydrofuran (5 mL) was added after cooling to<5° C. in an ice water bath. Potassium 2-methylpropan-2-olate (0.284 mL,0.284 mmol) was added dropwise, followed by addition of(E)-3,3-dimethyl-1-nitrobut-1-ene (3.66 g, 28.4 mmol) neat over 25minutes, maintaining an internal temperature<10° C. After the additionwas complete, the mixture was stirred for 15 minutes at the sametemperature. The mixture was diluted with methyl tert-butyl ether (200mL) and stirred with 100 mL of saturated aqueous ammonium chloride atroom temperature for 15 minutes. The layers were separated and theorganic layer was washed with saturated aqueous sodium bicarbonate andbrine, and dried over sodium sulfate. After filtration, the filtrate wasconcentrated and purified via flash chromatography, eluting with 0-25%ethyl acetate/heptanes over 220 g silica gel column to provide the titlecompound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 7.07 (ddt, J=16.1, 7.7,1.1 Hz, 2H), 6.82 (t, J=7.6 Hz, 1H), 5.31 (dd, J=5.7, 2.4 Hz, 1H), 4.44(dd, J=13.4, 5.7 Hz, 1H), 4.33 (qd, J=7.1, 1.6 Hz, 2H), 3.81 (dd,J=10.3, 7.2 Hz, 1H), 3.51 (dd, J=13.4, 10.5 Hz, 1H), 3.02 (q, J=1.1 Hz,2H), 2.89 (dd, J=7.2, 2.3 Hz, 1H), 1.51 (d, J=2.7 Hz, 6H), 1.37 (t,J=7.2 Hz, 3H), 1.08 (s, 9H); MS (ESI+) m/z 391.3 (M+H)⁺.

Example 256C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-4-nitropyrrolidine-2-carboxylate

To the solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-4-nitropyrrolidine-2-carboxylate(Example 256B, 2.0 g, 5.12 mmol) and triethylamine (2.142 mL, 15.37mmol) in dichloromethane (10 mL) was added cyclohexanecarbonyl chloride(0.754 mL, 5.63 mmol) at 0° C. The mixture was stirred at 0° C. for 30minutes. Dichloromethane (10 mL) and saturated aqueous NH₄Cl 95 mL) wereadded and the organic layer was separated. The solvent was removed andthe crude residue was purified via chromatography on a 40 g silica gelcartridge, eluting with ethyl acetate/hexanes at 0-70% gradient toprovide the title compound. MS (APCI+) m/z 501 (M+H)⁺.

Example 256D (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-oxopyrrolidine-1,2-dicarboxylate

A mixture of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (2.091 mL,13.98 mmol), carbon disulfide (1.201 mL, 19.97 mmol) in acetonitrile (20mL) was stirred at room temperature for 1 hour. To the solution wasadded Example 256C (2.0 g, 3.99 mmol) in 5 mL of CH₃CN at 0° C. Afterthe addition, the mixture was warmed to room temperature and stirred for2 hours. Ethyl acetate (200 mL) and brine (100 mL) were added. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. CH₃CN (100 mL) and 20% H₃PO₄ (100 mL) were added to thereaction mixture to hydrolyze the imine and the mixture was stirred atroom temperature for 4 hours. Ethyl acetate (200 mL) was added, and theorganic layer was washed with 80 mL of brine, dried over Na₂SO₄,filtered and concentrated. Purification via chromatography on a 220 gsilica gel cartridge eluting with a gradient of 0-30% ethylacetate/heptane provided the title compound. MS (APCI+) m/z 470 (M+1)⁺.

Example 256E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-4-hydroxypyrrolidine-2-carboxylate

To (2S,3R,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-4-oxopyrrolidine-2-carboxylate(Example 256D, 1.0 g, 2.129 mmol) in ethanol (5 mL) cooling in an icebath, sodium borohydride (0.105 g, 2.77 mmol) was added in portions. Themixture was stirred in an ice bath for 30 minutes. Saturated aqueousNH₄Cl (2 mL) was added and the solvent was removed under pressure. Theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The combined organic extracts was washed with brine,dried over sodium sulfate, filtered, and concentrated. The residue waspurified via chromatography on 12 g cartridge, eluting with ethylacetate/methanol (9:1) in heptane at a 0-40% gradient to provide thetitle compound. MS (APCI+) m/z 472 (M+H)⁺.

Example 256F(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)pyrrolidine-2-carboxylicacid

To 3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (Intermediate 4, 47.8mg, 0.187 mmol) and Example 256E (80 mg, 0.170 mmol) inN,N-dimethylformamide (2 mL) cooling in an ice bath, potassium2-methylpropan-2-olate (28.6 mg, 0.254 mmol) (0.35 mL, 1.0 M intetrahydrofuran) was added dropwise. The mixture was stirred the in icebath for 20 minutes, and it was allowed to warm to ambient temperature.The mixture was concentrated and methanol (2 mL) and 6N aqueous LiOH(0.5 mL) were added. The mixture was heated to 45° C. and stirredovernight. The pH was adjusted to 1˜2 by adding 2M aqueous HCl and themixture was filtered through a syringe filter. The filtrate was purifiedvia HPLC with the trifluoroacetic acid method to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.77 (d, J=2.5 Hz, 1H), 7.0(m, 1H), 7.03-6.97 (m, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.73 (t, J=7.5 Hz,1H), 5.33 (d, J=6.9 Hz, 1H), 4.37 (d, J=4.9 Hz, 1H), 4.29 (d, J=13.1 Hz,1H), 4.21 (dd, J=6.9, 4.4 Hz, 1H), 4.04 (d, J=13.1 Hz, 1H), 3.77 (d,J=0.8 Hz, 3H), 3.36-3.26 (m, 1H), 2.86 (s, 2H), 2.50 (d, J=4.8 Hz, 1H),2.29-2.15 (m, 3H), 1.99-1.80 (m, 4H), 1.71-1.60 (m, 2H), 1.49 (s, 2H),1.41 (s, 3H), 1.29 (s, 3H), 1.27-0.99 (m, 6H), 0.96 (s, 9H); MS (ESI+)m/z 619.3 (M+H)⁺.

Example 257(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 256, substituting Intermediate 8 for Intermediate 4 to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (dd, J=2.4, 1.2Hz, 1H), 7.69 (s, 1H), 7.14 (s, 1H), 6.95 (d, J=7.1 Hz, 1H), 6.69 (t,J=7.6 Hz, 1H), 5.34 (d, J=6.9 Hz, 1H), 4.44-4.35 (m, 2H), 4.27 (dd,J=6.9, 4.4 Hz, 1H), 4.09 (d, J=13.9 Hz, 1H), 3.89 (s, 3H), 2.78 (s, 2H),2.51 (t, J=4.6 Hz, 1H), 2.19 (s, 1H), 1.64 (d, J=12.7 Hz, 2H), 1.49 (s,2H), 1.40 (s, 3H), 1.29 (s, 1H), 1.26 (s, 3H), 1.24-1.00 (m, 5H), 0.98(s, 9H); MS (ESI+) m/z 633 (M+H)⁺.

Example 258(2S,3R,4S,5S)-1-(cyclohexanecarbonyl)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 258A (2S,3R,4S,5S)-ethyl5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-4-nitropyrrolidine-2-carboxylate

(2-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl)iron(0.378 g, 0.501 mmol) and copper (I) triflate dimer, benzene complex(0.097 g, 0.193 mmol) were dissolved in tetrahydrofuran (99 mL) that hadbeen sparged with a N₂ stream for 4 hours. The resulting solution wasstirred for 1.5 hours at ambient temperature, and (E)-ethyl2-((2-isopropylbenzylidene)amino)acetate (Core 13A) (9 g, 38.6 mmol) intetrahydrofuran (50 mL) was added after cooling to <5° C. in an icewater bath. Potassium 2-methylpropan-2-olate (0.386 mL, 0.386 mmol) 1Min tetrahydrofuran, was added dropwise, followed by addition of(E)-3-methoxy-3-methyl-1-nitrobut-1-ene (5.60 g, 38.6 mmol) neat over 25minutes, maintaining an internal temperature<10° C. After the additionwas complete, the mixture was stirred for 15 minutes at the sametemperature. The mixture was diluted with methyl tert-butyl ether (200mL) and stirred with 100 mL of saturated aqueous ammonium chloride atambient temperature for 15 minutes. The layers were separated and theorganic layer was washed with saturated aqueous sodium bicarbonate andbrine, dried over sodium sulfate, filtered, and concentrated in vacuo.The crude product was purified via flash chromatography, eluting with0-25% ethyl acetate/heptanes over a 220 g silica gel column to providethe title compound; MS (ESI+) m/z 379 (M+H)⁺.

Example 258B (2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-4-nitropyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-Ethyl5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-4-nitropyrrolidine-2-carboxylatefrom Example 258A (10.2 g, 27.0 mmol) was dissolved in ethyl acetate(67.4 mL) and saturated aqueous sodium bicarbonate (67.4 mL) was added.While stirring vigorously, allyl chloroformate (3.02 mL, 28.3 mmol) wasadded via additional funnel over 10 minutes. The mixture was stirred for20 minutes at ambient temperature and the layers were separated. Theorganic layer was washed with water and brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude material waspurified via flash chromatography, eluting with 0-25% ethylacetate/heptanes on a 220 g silica gel column to provide the titlecompound. MS (ESI+) m/z 463 (M+H)⁺.

Example 258C (2S,3S,5S)-1-allyl 2-ethyl5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-4-oxopyrrolidine-1,2-dicarboxylate

Into a 500 mL flask was charged DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)(12.65 mL, 84 mmol) and carbon disulfide (7.23 mL, 120 mmol) inacetonitrile (48.0 mL) and the mixture was stirred at ambienttemperature for 1 hour. To the resulting solution at 0° C. was added(2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-4-nitropyrrolidine-1,2-dicarboxylatefrom Example 258B (11.09 g, 23.98 mmol) in 5 mL of CH₃CN. The reactionwas allowed to warm to room temperature over 2 hours and 100 mL of CH₃CNand 100 mL 20% aqueous H₃PO₄ were added. The mixture was stirred atambient temperature for 16 hours. Ethyl acetate (200 mL) and 100 mLbrine were added. The organic layer was filtered and concentrated.Further hydrolysis was done for 4 hours at ambient temperature using 100mL CH₃CN and 100 mL 20% aqueous H₃PO₄. Ethyl acetate (200 mL) and 100 mLbrine were added. The organic layer was separated and washed with 80 mLof brine. The mixture was filtered and concentrated. The residue waschromatographed using a 220 g silica gel cartridge with a gradient of0-30% ethyl acetate/heptanes to provide the title compound; MS (ESI+)m/z 432 (M+H)⁺.

Example 258D (2S,3R,4S,5S)-1-allyl 2-ethyl4-hydroxy-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylate

(2S,3S,5S)-1-Allyl 2-ethyl5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-4-oxopyrrolidine-1,2-dicarboxylatefrom Example 258C (2.58 g, 5.98 mmol) was dissolved in ethanol (29.9 mL)and the resulting solution was cooled to <−10° C. in a brine ice bathbefore addition of sodium borohydride (0.249 g, 6.58 mmol) in oneportion. After 40 minutes, the reaction was quenched with the slowaddition of acetone over 10 minutes. The reaction was concentrated invacuo and the residual material was partitioned between saturatedaqueous sodium bicarbonate and methyl tert-butyl ether. The organicextracts were washed with brine, dried over sodium sulfate, filtered,and concentrated. The residue was purified via flash chromatography,eluting with 0-30% ethyl acetate/heptanes to provide the title compound.MS (ESI+) m/z 434 (M+H)⁺.

Example 258E (2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-1-Allyl 2-ethyl4-hydroxy-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylatefrom Example 258D (500 mg, 1.153 mmol) and3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (436 mg, 1.615mmol) were dissolved in dry N,N-dimethylformamide (7 mL). After coolingin an ice bath, potassium 2-methylpropan-2-olate (1.615 mL, 1.615 mmol)as a 1M solution in tetrahydrofuran was added dropwise over 4 minutes.After 30 minutes, the mixture was quenched with saturated aqueous NH₄Clsolution and extracted with dichloromethane. The organic solvent wasevaporated. The crude residue was loaded onto a 24 g silica gel columnand eluted with 0-70% ethyl acetate/heptanes over 20 minute to providethe title compound. ¹H NMR (501 MHz, DMSO-d₆) δ ppm 8.45-8.29 (m, 1H),7.93 (s, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.03 (d,J=7.6 Hz, 2H), 5.71 (d, J=153.3 Hz, 1H), 5.36 (s, 1H), 5.31-4.80 (m,1H), 4.65 (d, J=2.0 Hz, 1H), 4.50 (m, 1H), 4.36 (d, J=14.4 Hz, 1H), 4.32(d, J=5.6 Hz, 1H), 4.10 (qd, J=7.1, 2.1 Hz, 2H), 3.85 (d, 4H), 3.19 (s,3H), 2.82 (s, 1H), 1.27 (d, J=31.0 Hz, 6H), 1.19 (s, 6H), 1.15-1.07 (m,3H); MS (APCI+) m/z 613 (M+H)⁺.

Example 258F (2S,3R,4S,5S)-ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylatefrom Example 258E (370 mg, 0.594 mmol) in acetonitrile/water (4.29 mL,10:1) was added tetrakis(triphenylphosphine)palladium(0) (15.11 mg,0.013 mmol) and diethylamine (0.123 mL, 1.188 mmol). The mixture wasstirred at ambient temperature for 90 minutes. The mixture wasconcentrated to a 1 mL volume. Dichloromethane and water were added, andthe organic layer was washed with brine, dried over Na₂SO₄, filtered,and concentrated. Purified via chromatography, eluting on 24 g cartridgewith a gradient 0-70% ethyl acetate/heptanes over 20 minutes providedthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.34 (d, J=1.4 Hz,1H), 7.57 (dd, J=7.8, 1.4 Hz, 1H), 7.19 (td, J=7.5, 1.9 Hz, 2H), 7.13(td, J=7.5, 1.4 Hz, 1H), 7.02 (td, J=7.5, 1.4 Hz, 1H), 4.38 (dd, J=8.0,4.6 Hz, 1H), 4.24 (d, J=14.1 Hz, 1H), 4.10 (p, J=7.0 Hz, 2H), 4.00 (dd,J=4.6, 1.7 Hz, 1H), 3.80 (s, 3H), 3.74 (d, J=14.1 Hz, 1H), 3.67 (t,J=7.1 Hz, 1H), 3.12 (s, 5H), 2.58 (dd, J=6.9, 1.7 Hz, 1H), 1.21-1.09 (m,16H); MS (APCI+) m/z 539 (M+H)⁺.

Example 258G (2S,3R,4S,5S)-ethyl1-(cyclohexanecarbonyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylate

A solution of (2S,3R,4S,5S)-ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylatefrom Example 258F (100 mg, 0.186 mmol) and triethylamine (0.052 mL,0.371 mmol) in dichloromethane (1 mL) at 25° C. was treated withcyclohexanecarbonyl chloride (0.031 mL, 0.232 mmol) dropwise, stirredfor 2 hours, washed with saturated aqueous NaHCO₃ (3 mL) and with 1Naqueous NH₄OH (1 mL) solution to convert any leftover acid chloride tothe corresponding amide, and concentrated. The residue was dissolved in1 mL dichloromethane and loaded onto a 12 g column eluting with agradient of 0-70% ethyl acetate/heptanes over a period of 20 minutes toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.28 (d,J=2.4 Hz, 1H), 7.91 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.14 (d, J=12.0 Hz,2H), 7.01 (t, J=7.5 Hz, 1H), 5.45 (d, J=5.6 Hz, 1H), 4.79 (d, J=1.8 Hz,1H), 4.38-4.20 (m, 2H), 4.10 (qd, J=7.1, 2.3 Hz, 2H), 3.86 (s, 3H), 3.82(d, J=13.9 Hz, 1H), 3.28-3.20 (m, 1H), 3.19 (s, 3H), 2.77 (s, 1H), 2.11(s, 1H), 1.63 (t, J=13.4 Hz, 3H), 1.47 (s, 2H), 1.30-1.25 (m, 9H), 1.23(m, 2H), 1.18 (d, J=6.8 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.06 (t, J=11.6Hz, 2H); MS (APCI+) m/z 648 (M+H)⁺.

Example 258H(2S,3R,4S,5S)-1-(cyclohexanecarbonyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl1-(cyclohexanecarbonyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylatefrom Example 258G (107 mg, 0.165 mmol) in tetrahydrofuran (0.5 mL),methanol (0.500 mL) and water (0.500 mL) was added lithium hydroxidehydrate (48.5 mg, 1.155 mmol) and the reaction was heated at 45° C. for16 hours. The solvent was removed under a stream of nitrogen. Water (2mL) was added to the crude material and the mixture was extracted with 5mL heptane (discarded). The desired product was extracted into diethylether and the mixture was concentrated. Water was added and the mixturewas acidified with 1M aqueous HCl (0.02 mL) to pH˜6. The mixture wasfiltered to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.24 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.08 (d,1H), 7.04 (s, 1H), 6.96 (m, 1H), 5.43 (d, J=6.2 Hz, 1H), 4.47 (s, 1H),4.35 (d, J=14.2 Hz, 1H), 4.24 (s, 1H) 3.87 (m, 4H), 3.21 (m, 4H), 3.02(bs, 2H) 1.65 (bs, 2H), 1.52 (bs, 2H), 1.27 (d, J=6.7 Hz, 3H), 1.23 (d,J=6.3 Hz, 8H), 1.12 (d, J=6.8 Hz, 3H), 1.09 (bs, 3H); MS (APCI+) m/z 621(M+H)⁺.

Example 259(2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 259A (2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-Ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylatefrom Example 258F (100 mg, 0.186 mmol) was dissolved in toluene (0.5 mL)and triethylamine (0.065 mL, 0.464 mmol) was added, followed by slowaddition of isopropyl carbonochloridate (0.111 mL, 0.223 mmol) solutionafter cooling in an ice water bath to ˜10° C. The addition was at such arate that the temperature was maintained at or below ambient temperatureduring the addition (2 minutes). After the addition was complete, themixture was removed from water bath and stirred at ambient temperaturefor 2 hours. The mixture was diluted with diethyl ether and stirred withsaturated aqueous sodium bicarbonate for 20 minutes before separatingthe layers. The organic layer was washed with 1M aqueous HCl×3 andbrine, dried over sodium sulfate, filtered and concentrated. The residuewas dissolved in 1 mL heptanes and loaded onto a 12 g cartridge elutingwith a gradient of 0-60% ethyl acetate/heptanes over a period of 20minutes to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.36 (dd, J=2.5, 1.2 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.18 (dd, J=7.9,1.4 Hz, 1H), 7.11 (td, J=7.5, 1.5 Hz, 2H), 7.01 (td, J=7.5, 1.4 Hz, 1H),5.30 (s, 1H), 4.57 (d, J=2.0 Hz, 1H), 4.35 (d, J=14.5 Hz, 1H), 4.32-4.28(m, 1H), 4.10 (qd, J=7.1, 4.7 Hz, 2H), 3.85 (s, 4H), 3.31 (m, 1H), 3.19(s, 4H), 2.79 (s, 1H), 1.29 (s, 3H), 1.22 (d, J=7.0 Hz, 6H), 1.13 (t,J=7.1 Hz, 6H), 0.97 (s, 3H), 0.62 (s, 3H); MS (ESI+) m/z 625 (M+H)⁺.

Example 259B(2S,3R,4S,5S)-1-(isopropoxycarbonyl)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-2-ethyl 1-isopropyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylatefrom Example 259A (92 mg, 0.147 mmol) in tetrahydrofuran (0.5 mL),methanol (0.500 mL) and water (0.500 mL) was added lithium hydroxidehydrate (43.3 mg, 1.031 mmol) and the reaction was heated at 45° C. for16 hours. The solvent was removed under a stream of nitrogen. Water (2mL) was added to the crude material, and the mixture was extracted with5 mL heptane (discarded). The desired product was extracted into diethylether and concentrated. The mixture was acidified with 1M aqueous HCl(0.02 mL) to pH˜6 and filtered to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.34 (d, J=2.3 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H),7.17 (dd, J=7.8, 1.4 Hz, 1H), 7.10 (td, J=7.5, 1.4 Hz, 1H), 7.00 (m,2H), 5.28 (d, J=5.5 Hz, 1H), 4.67-4.52 (m, 1H), 4.50-4.44 (m, 1H), 4.36(d, J=14.6 Hz, 1H), 4.28 (d, J=5.7 Hz, 1H), 3.85 (m, 4H), 3.19 (s, 3H),3.15 (m, 1H), 2.81 (s, 1H), 1.27 (s, 3H), 1.21 (d, J=6.2 Hz, 6H), 1.12(d, J=6.7 Hz, 3H), 0.97 (bs, 3H), 0.61 (bs, 3H); MS (APCI+) m/z 597(M+H)⁺.

Example 260(2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 260A (2S,3R,4S,5S)-ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylatefrom Example 258F (100 mg, 0.186 mmol) in dichloromethane (1.9 mL) at 0°C. was added triethylamine (0.116 mL, 0.836 mmol) followed by additionof (S)-tetrahydro-2H-pyran-2-carbonyl chloride (46.9 mg, 0.316 mmol) asa solution in 1 mL dichloromethane. After stirring for 15 minutes, thereaction was quenched with 5 mL of saturated aqueous sodium bicarbonateand the crude material was chromatographed using a 24 g silica gelcartridge with a gradient of 0-65% ethyl acetate/heptanes over a periodof 20 minutes to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.27 (dd, J=2.5, 1.1 Hz, 1H), 7.96 (dd, J=7.9, 1.5 Hz, 1H), 7.22 (d,J=7.7 Hz, 1H), 7.15 (s, 2H), 7.02 (d, J=7.8 Hz, 1H), 5.64 (s, 1H), 4.80(d, J=1.8 Hz, 1H), 4.35 (d, 1H), 4.28 (d, J=5.3 Hz, 1H), 4.09 (qd,J=7.1, 2.2 Hz, 2H), 3.86 (s, 3H), 3.81 (d, J=13.9 Hz, 1H), 3.73 (d,J=11.2 Hz, 1H), 3.21 (m, 4H), 3.15 (d, 1H), 2.80 (m, 1H), 2.73 (d, J=1.7Hz, 1H), 1.67 (m, 1H), 1.54 (m, 2H), 1.38 (m, 3H), 1.29 (d, J=6.7 Hz,3H), 1.26 (d, J=5.9 Hz, 6H), 1.14 (t, J=7.0 Hz, 6H); MS (APCI+) m/z 651(M+H)⁺.

Example 260B(2S,3R,4S,5S)-5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid

To a solution of (2S,3R,4S,5S)-ethyl5-(2-isopropylphenyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-3-(2-methoxypropan-2-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 260A (98 mg, 0.151 mmol) in tetrahydrofuran (0.5 mL),methanol (0.500 mL) and water (0.500 mL) was added lithium hydroxidehydrate (44.2 mg, 1.054 mmol) and the reaction was heated at 45° C. for16 hours. The solvent was removed under a stream of nitrogen. Water (2mL) was added to the crude material, and the mixture was extracted with5 mL heptane (discarded). The desired product was extracted into diethylether and the mixture was concentrated. Water was added (15 mL), and themixture was acidified with 1M aqueous HCl (0.1 mL) to pH˜6, andfiltered. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (d, J=2.4 Hz, 1H), 8.03(dd, J=7.9, 1.4 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.14 (d, 1H), 7.10 (s,1H), 7.01 (m, 1H), 5.64 (s, 1H), 4.73 (d, J=1.8 Hz, 1H), 4.34 (d, J=14.1Hz, 1H), 4.28 (d, J=5.9 Hz, 1H), 3.87 (m, 4H), 3.75 (d, J=11.4 Hz, 1H),3.63 (bs, 1H), 3.21 (m, 4H), 3.08 (m, 2H), 1.68 (d, J=13.2 Hz, 1H), 1.56(m, 2H), 1.37 (m, 3H), 1.29 (d, J=6.7 Hz, 3H), 1.25 (s, 6H), 1.12 (d,J=6.8 Hz, 3H); MS (APCI+) m/z 623 (M+H)⁺.

Example 261(2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 261A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-(2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

A mixture of Example 249D ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)allyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(120 mg, 0.190 mmol) and 10% Pd/C (25 mg, 0.023 mmol) in ethanol (2 mL)was stirred under an atmosphere of H₂ (balloon) for 90 minutes. Themixture was diluted with ethyl acetate (25 mL), stirred for 5 minutes,and filtered to remove the solids. The filtrate was concentrated todryness to provide the title compound. LC/MS (ESI+) m/z 634 (M+H)⁺.

Example 261B(2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 261A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-(2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(37 mg, 0.058 mmol) in tetrahydrofuran (1 mL) was diluted with methanol(0.5 mL), diluted with water (1 mL), treated with lithium hydroxidehydrate (49.0 mg, 1.168 mmol), stirred at 45° C. overnight, cooled,treated with 1 M aqueous HCl (3 mL) and extracted with ethyl acetate (50mL). The ethyl acetate layer was washed with brine, dried (MgSO₄),filtered, concentrated and chromatographed on silica gel, eluting with agradient of 20% to 50% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptane toprovide the title compound. ¹H NMR (400 MHz, DMSO, 120° C.) δ ppm8.00-7.95 (m, 1H), 7.48-7.42 (m, 1H), 7.22-7.01 (m, 5H), 5.48 (s, 1H),4.59 (dd, J=2.1, 5.5 Hz, 1H), 4.08-4.04 (m, 1H), 3.81-3.75 (m, 1H), 3.82(s, 1.5H), 3.78 (s, 1.5H), 3.40 (s, 1H), 3.23 (dd, J=5.4, 9.0 Hz, 1H),3.19-3.13 (m, 1H), 3.04-2.72 (m, 3H), 2.39-2.35 (m, 1H), 2.36 (s, 1.5H),2.34 (s, 1.5H), 1.74-1.62 (m, 1H), 1.53 (d, J=11.9 Hz, 1H), 1.32 (d,J=23.8 Hz, 3H), 0.99 (s, 4H), 0.98 (s, 5H), 0.84 (d, J=6.7 Hz, 1.5H),0.78 (d, J=7.0 Hz, 1.5H); LC/MS (ESI+) m/z 606 (M+H)⁺.

Example 262(2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 262A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((S)-2,3-dihydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

A solution of Example 249D ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)allyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(290 mg, 0.459 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) wastreated with a 4% solution of osmium tetroxide in water (146 mg, 0.023mmol), treated with sodium periodate (196 mg, 0.918 mmol), and stirredovernight at room temperature. The mixture was treated with more 4%osmium tetroxide in water (300 mg, 0.046 mmol) and stirred at roomtemperature overnight. The mixture was partitioned between ethyl acetate(50 mL) and 1 M aqueous HCl (15 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (50 mL). The combinedethyl acetate layers were dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 10% to 100%ethyl acetate in heptane to provide three isolated products. The firstproduct to elute was ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((S)-2,3-dihydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate;LC/MS (ESI+) m/z 634 (M+H)⁺. The second product to elute was ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((S)-2,3-dihydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate;LC/MS (ESI+) m/z 666 (M+H)⁺. The third product to elute was ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((R)-2,3-dihydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate;LC/MS (ESI+) m/z 666 (M+H)⁺. The title compound was the second productto elute, Example 262A.

Example 262B(2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 262A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((S)-2,3-dihydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(30 mg, 0.045 mmol) in tetrahydrofuran (1 mL) was diluted with methanol(0.5 mL), diluted with water (1 mL), treated with lithium hydroxidehydrate (18.91 mg, 0.451 mmol), stirred at room temperature for 90minutes, and heated to 45° C. 2.5 for hours. The mixture was treatedwith 1 M aqueous HCl (3 mL) and extracted twice with ethyl acetate (2×30mL). The combined ethyl acetate layers were washed with brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 10% to 100% [200:1:1 ethyl acetate:HCOOH:H₂O]in heptane to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆, 120°C.) δ ppm 7.90 (d, J=7.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.48 (dd,J=2.5, 8.5 Hz, 1H), 7.17-7.05 (m, 3H), 7.02 (d, J=8.6 Hz, 1H), 5.46 (bs,1H), 4.56 (d, J=2.0 Hz, 1H), 4.10 (d, J=5.8 Hz, 1H), 3.80-3.72 (m, 4H),3.40-3.35 (m, 3H), 3.24 (d, J=9.9 Hz, 1H), 3.07-2.79 (m, 2H), 2.37 (bs,1H), 2.34 (s, 3H), 1.73-1.63 (m, 1H), 1.57-1.46 (m, 1H), 1.44-1.25 (m,4H), 0.96 (s, 9H); LC/MS (ESI+) m/z 638 (M+H)⁺.

Example 263(2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 263A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((R)-2,3-dihydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

The procedure described for Example 262A provided the title compound asthe third product to elute. LC/MS (ESI+) m/z 666 (M+H)⁺.

Example 263B(2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 263A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((R)-2,3-dihydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(30 mg, 0.045 mmol) in tetrahydrofuran (1 mL) was diluted with methanol(0.5 mL), diluted with water (1 mL), treated with lithium hydroxidehydrate (18.91 mg, 0.451 mmol), stirred at room temperature for 90minutes, and heated to 45° C. for 2.5 hours. The mixture was treatedwith 1 M aqueous HCl (3 mL) and extracted twice with ethyl acetate (2×30mL). The combined ethyl acetate layers were washed with brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 10% to 100% [200:1:1 ethyl acetate:HCOOH:H₂O]in heptane to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆, 120°C.) δ ppm 7.82 (d, J=7.7 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.47 (dd,J=2.5, 8.6 Hz, 1H), 7.08-7.02 (m, 2H), 7.02-6.94 (m, 2H), 5.43 (bs, 1H),4.59 (s, 1H), 4.10 (d, J=5.8 Hz, 1H), 3.80-3.72 (m, 4H), 3.55 (d, J=10.0Hz, 1H), 3.45 (d, J=11.2 Hz, 1H), 3.40 (d, J=11.2 Hz, 1H), 3.30 (d,J=10.0 Hz, 1H), 3.12-2.66 (m, 2H), 2.35 (s, 1H), 2.26 (s, 3H), 1.72-1.25(m, 6H), 0.98 (s, 9H); LC/MS (ESI+) m/z 638 (M+H)⁺.

Example 264(2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxoethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 249((2S,3R,4S,5S)-3-(tert-butyl)-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)allyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylicacid) (48 mg, 0.080 mmol) in tetrahydrofuran (2 mL) was diluted withwater (1 mL), treated with 4% solution of osmium tetroxide in water(50.5 mg, 7.95 μmol), cooled to 0° C., treated with sodium periodate(51.0 mg, 0.239 mmol) and stirred overnight at room temperature. Themixture was partitioned between ethyl acetate (30 mL) and 1 M aqueousHCl (5 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (30 mL). The combined ethyl acetate layerswere washed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 20% to 50%[200:1:1 ethyl acetate:HCOOH:H₂O] in heptane to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.00 (d, J=6.7 Hz,1H), 7.77 (ddd, J=0.8, 2.5, 8.8 Hz, 1H), 7.64 (d, J=2.5 Hz, 1H), 7.22(d, J=8.8 Hz, 1H), 7.15-7.07 (m, 3H), 5.44 (bs, J=29.9 Hz, 1H), 4.60 (d,J=2.0 Hz, 1H), 4.20 (d, J=5.7 Hz, 1H), 3.95-3.84 (m, 2H), 3.81 (s, 3H),3.81-3.75 (m, 2H), 2.54 (d, J=2.1 Hz, 1H), 2.38 (s, 3H), 2.37-2.34 (m,1H), 1.72-1.26 (m, 6H), 1.01 (s, 9H); LC/MS (ESI+) m/z 606 (M+H)⁺.

Example 265(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-{[(1,1,1-trifluoropropan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 265A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

To (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate(Example 285C, 800 mg, 1.841 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (Intermediate 4, 472 mg,1.841 mmol) in N,N-dimethylformamide (5 mL) cooling in an ice bath,potassium 2-methylpropan-2-olate (310 mg, 2.76 mmol) (2.8 mL, 1.0 M intetrahydrofuran) was added dropwise, and the mixture was stirred in anice bath for 20 minutes. The mixture was allowed to warm to ambienttemperature. Dichloromethane (30 mL) was added and the mixture waswashed with brine, dried over MgSO₄, filtered, and concentrated.Purification via chromatography on a 12 g silica gel cartridge, elutingwith ethyl acetate/methanol (9:1) in heptane at 0-45% gradient toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03-8.00(m, 1H), 7.93 (d, J=5.8 Hz, 1H), 7.75 (d, J=5.8 Hz, 1H), 6.85-6.80 (m,2H), 5.75 (m, 1H), 5.27-5.21 (m, 1H), 5.20 (d, J=5.8 Hz, 1H), 5.09-5.05(m, 1H), 5.03 (t, J=1.6 Hz, 1H), 4.45 (dd, J=21.6, 2.4 Hz, 3H),4.30-4.22 (m, 2H), 4.10-4.03 (m, 2H), 3.93 (dt, J=13.0, 0.9 Hz, 1H),3.75 (s, 3H), 3.33 (q, J=8.5 Hz, 1H), 2.28-2.18 (m, 2H), 2.00-1.78 (m,4H), 1.28 (d, J=6.1 Hz, 3H), 1.21 (d, J=6.1 Hz, 3H), 1.11 (t, J=7.1 Hz,3H), 1.00 (s, 9H); MS (ESI+) m/z 610 (M+H)⁺.

Example 265B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate(480 mg, 0.787 mmol) and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(246 mg, 1.574 mmol) in ethyl acetate/dichloromethane (8 mL, 1:1) wasadded tetrakis(triphenylphosphine)palladium(0) (16.24 mg, 0.016 mmol).The mixture was stirred at room temperature for 20 minutes.Dichloromethane (20 mL) and water (10 mL) were added and the organiclayer was washed with brine, dried over MgSO₄ and concentrated. Theresidue was purified by chromatography on a 24 g silica gel cartridge,eluting with ethyl acetate in heptane, to provide the title compound. MS(APCI+) m/z 526 (M+H)⁺.

Example 265C(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-{[(1,1,1-trifluoropropan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

To a solution of Example 265B (390 mg, 0.742 mmol) in toluene (5 mL) andsaturated aqueous sodium bicarbonate (5 mL) was added1,1,1-trifluoropropan-2-yl carbonochloridate (262 mg, 1.484 mmol)dropwise at room temperature. The mixture was stirred at roomtemperature for 30 minutes. Dichloromethane (20 mL) and water (10 mL)were added and the organic layer was washed with brine, dried over MgSO₄filtered, and concentrated. Purification by chromatography on a 24 gcartridge, eluting with ethyl acetate in heptane at a 0-40% gradient toyield (2S,3R,4S,5S)-2-ethyl 1-(1,1,1-trifluoropropan-2-yl)3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate,which was dissolved in methanol (2 mL) and 6 M LiOH (0.5 mL) and stirredat 50° C. overnight. The pH was adjusted to 1˜2 by adding 2M aqueous HCland concentrated to dryness. The residue was loaded onto a 12 gramsilica gel cartridge, eluting with ethyl acetate/methanol (9:1) inheptane at a 0-50% gradient to provide the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.09 (dd, J=10.4, 8.2 Hz, 1H), 7.94 (ddd, J=6.7,4.9, 1.9 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 6.86-6.78 (m, 2H), 5.28-5.18(m, 2H), 5.13 (pd, J=6.8, 5.1 Hz, 1H), 4.39 (d, J=2.2 Hz, 1H), 4.28 (d,J=13.1 Hz, 1H), 4.24 (dd, J=5.9, 1.6 Hz, 1H), 3.95 (d, J=13.1 Hz, 1H),3.75 (s, 3H), 3.32 (p, J=8.5 Hz, 1H), 2.5 (m, 1H), 2.33-2.21 (m, 2H),1.91 (dtt, J=22.6, 15.3, 7.6 Hz, 4H), 1.35-1.26 (m, 3H), 1.27-1.23 (m,3H), 1.21 (d, J=6.1 Hz, 3H), 1.06 (d, J=6.4 Hz, 1H), 1.00 (s, 9H); MS(ESI+) m/z 638.1 (M+H)⁺.

Example 266(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2R)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid Example 266A (2S,3R,4S,5S)-2-ethyl1-((R)-1,1,1-trifluoropropan-2-yl)3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

To (R)-1,1,1-trifluoropropan-2-ol [CAS#17628-73-8] (0.397 mL, 4.38 mmol)and bis(trichloromethyl) carbonate (429 mg, 1.447 mmol) in diethyl ether(10 mL) cooling at −10° C. was added triethylamine (0.611 mL, 4.38 mmol)dropwise. The reaction mixture was warmed to 0° C. and stirred for 2hours, and stirred at room temperature for 2 hours. The mixture wasadded to a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate(Example 169A, 550 mg, 1.569 mmol) in toluene and saturated aqueoussodium bicarbonate (20 mL, 1:1) dropwise. The mixture was stirred atroom temperature for 20 minutes. Ethyl acetate (20 mL) was added, andthe organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography on a 24 gsilica gel cartridge, eluting with ethyl acetate in heptane, at a 0-40%gradient to provide the title compound. MS (APCI+) m/z 491 (M+H)⁺.

Example 266B(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2R)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid

To Example 266A (60 mg, 0.122 mmol) and3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine (Intermediate 4, 34.5 mg,0.135 mmol) in N,N-dimethylformamide (2 mL) cooling in an ice bath,potassium 2-methylpropan-2-olate (20.59 mg, 0.183 mmol) (2.8 mL, 1.0 Min tetrahydrofuran) was added dropwise. The mixture was stirred in anice bath for 20 minutes, and allowed to warm to ambient temperature. Theorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was dissolved in methanol (2 mL) and aqueousLiOH (6M, 0.5 mL) and stirred at 50° C. overnight. The pH was adjustedto 1˜2 by adding 2M aqueous HCl and was concentrated. The residue wasloaded onto a 12 gram silica gel cartridge, eluting with ethylacetate/methanol (9:1) in heptane at a 0-45% gradient to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.07 (d, J=1.9 Hz, 1H),7.93 (m, 1H), 7.87-7.73 (m, 1H), 6.94-6.80 (m, 2H), 5.33-5.22 (m, 1H),5.22-5.09 (m, 2H), 4.40 (d, J=2.3 Hz, 1H), 4.28 (d, J=13.1 Hz, 1H), 3.96(t, J=0.8 Hz, 1H), 3.75 (d, J=0.6 Hz, 3H), 3.34 (t, J=8.2 Hz, 1H), 2.21(s, H), 2.33-2.21 (m, 2H), ), 2.07-1.82 (m, 4H), 1.28 (s, 1H), 1.25 (dd,J=5.9, 1.6 Hz, 3H), 1.00 (s, 9H); MS (ESI+) m/z 638.3 (M+H)⁺.

Example 267(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid

The title compound was synthesized using the same procedure as describedin Example 266A and 266B, replacing (R)-1,1,1-trifluoropropan-2-ol with(S)-1,1,1-trifluoropropan-2-ol [CAS#3539-97-7] to provide titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.11 (dd, J=7.4, 1.9 Hz, 1H),7.95 (dd, J=4.9, 1.9 Hz, 1H), 7.76 (dd, J=2.4, 0.8 Hz, 1H), 6.85 (dt,J=2.4, 0.8 Hz, 1H), 6.82 (dd, J=7.4, 4.9 Hz, 1H), 5.23 (dt, J=12.1, 6.1Hz, 2H), 5.12 (p, J=6.7 Hz, 1H), 4.39 (d, J=2.3 Hz, 1H), 4.27 (d, J=13.1Hz, 1H), 4.23 (dd, J=5.8, 1.5 Hz, 1H), 3.95 (dt, J=13.1, 0.9 Hz, 1H),3.75 (s, 3H), 3.37-3.29 (m, 1H), 2.33-2.20 (m, 2H), 2.06-1.82 (m, 4H),1.28-1.24 (m, 3H), 1.21 (d, J=6.2 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H), 1.00(s, 9H); MS (ESI+) m/z 638.2 (M+H)⁺.

Example 268(2S,3R,4S,5S)-3-tert-butyl-4-{2-hydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 268A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-(2-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxoethoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

The procedure described for Example 262A provided the titled compound asthe first product to elute. LC/MS (ESI+) m/z 634 (M+H)⁺.

Example 268B ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-(2-hydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)ethoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

A mixture of Example 268A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-(2-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxoethoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(50 mg, 0.079 mmol) in ethanol (1 mL) was treated with NaBH₄ (5.97 mg,0.158 mmol), stirred at room temperature for 30 minutes, treated with 1M aqueous HCl (2 mL) and extracted with ethyl acetate (50 mL). The ethylacetate layer was washed with brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel, eluting with a gradientof 20% to 50% ethyl acetate in heptane to provide the title compound.LC/MS (ESI+) m/z 635 (M+H)⁺.

Example 268C(2S,3R,4S,5S)-3-tert-butyl-4-{2-hydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 268B ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-(2-hydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)ethoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(30 mg, 0.047 mmol) in tetrahydrofuran (1 mL) was diluted with methanol(0.5 mL), diluted with water (1 mL), treated with lithium hydroxidehydrate (39.6 mg, 0.944 mmol), stirred at 45° C. for 8 hours, andstirred overnight at room temperature. The mixture was partitionedbetween 1 M aqueous HCl (3 mL) and ethyl acetate (50 mL). The ethylacetate layer was washed with brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel, eluting with a gradientof 20% to 50% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptane to providethe title compound. ¹H NMR (400 MHz, DMSO, 120° C.) δ ppm 7.99-7.95 (m,1H), 7.51-7.46 (m, 2H), 7.13-7.01 (m, 4H), 5.46 (bs, 1H), 4.71 (dd,J=4.0, 6.7 Hz, 0.5H), 4.60 (dd, J=3.9, 7.0 Hz, 0.5H), 4.56 (dd, J=2.2,5.0 Hz, 1H), 4.19 (d, J=5.8 Hz, 0.5H), 4.16 (d, J=5.9 Hz, 0.5H), 3.82(s, 1.5H), 3.82-3.75 (m, 2H), 3.77 (s, 1.5H), 3.09 (dd, J=4.0, 10.6 Hz,1H), 3.02 (d, J=7.1 Hz, 0.5H), 2.99 (d, J=7.1 Hz, 0.5H), 2.97-2.74 (m,2H), 2.45 (bs, 0.5H), 2.39 (bs, 0.5H), 2.37 (s, 1.5H), 2.34 (s, 1.5H),1.74-1.19 (m, 6H), 1.00 (s, 4.5H), 1.00 (s, 4.5H); LC/MS (ESI+) m/z 608(M+H)⁺.

Example 269(2S,3R,4S,5S)-3-tert-butyl-4-{2-methoxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 268B ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-(2-hydroxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)ethoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(6 mg, 9.44 μmol) in N,N-dimethylformamide (0.5 mL) was treated withiodomethane (5.90 μL, 0.094 mmol), cooled to −20° C., treated dropwisewith 1 M potassium tert-butoxide in tetrahydrofuran (18.88 μL, 0.019mmol), stirred at −20° C. for 15 minutes, warmed to 0° C., stirred for45 minutes, treated with more 1 M potassium tert-butoxide intetrahydrofuran (18.88 μL, 0.019 mmol), stirred at room temperature for15 minutes, treated with 1 M aqueous HCl (3 mL) and extracted withmethyl tert-butyl ether (50 mL). The methyl tert-butyl ether layer waswashed with water (20 mL), washed with brine, dried (MgSO₄), filtered,and concentrated. The residue was taken up in tetrahydrofuran (0.5 mL),diluted with methanol (0.25 mL), diluted with water (0.5 mL), treatedwith lithium hydroxide hydrate (7.92 mg, 0.189 mmol), stirred at 45° C.overnight, cooled, treated with 1 M aqueous HCl (3 mL) and extractedwith ethyl acetate (30 mL). The ethyl acetate layer was washed withbrine, dried (MgSO₄), filtered, concentrated and chromatographed onsilica gel, eluting with a gradient of 20% to 50% [200:1:1 ethylacetate:HCOOH:H₂O] in heptane to provide the title compound,(2S,3R,4S,5S)-3-(tert-butyl)-4-(2-methoxy-2-(2-methoxy-5-(trifluoromethyl)phenyl)ethoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.02-7.96 (m, 1H),7.57-7.51 (m, 1H), 7.36 (d, J=2.5 Hz, 0.5H), 7.33 (d, J=2.5 Hz, 0.5H),7.17-7.04 (m, 4H), 5.48 (bs, 1H), 4.58 (d, J=2.2 Hz, 1H), 4.31 (dd,J=3.3, 6.8 Hz, 0.5H), 4.22 (dd, J=3.2, 7.1 Hz, 0.5H), 4.17 (d, J=6.0 Hz,0.5H), 4.14 (d, J=6.0 Hz, 0.5H), 3.85 (s, 1.5H), 3.80 (s, 1.5H),3.79-3.75 (m, 1H), 3.14-3.09 (m, 1H), 3.02 (s, 1.5H), 2.99 (s, 1.5H),2.95-2.80 (m, 2H), 2.42 (bs, 1H), 2.38 (s, 1.5H), 2.35 (s, 1.5H),1.73-1.22 (m, 6H), 1.00 (s, 4.5H), 0.99 (s, 4.5H), 0.90-0.81 (m, 1H);LC/MS (ESI+) m/z 622 (M+H)⁺.

Example 270(2S,3R,4S,5S)-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-3-(2-methoxypropan-2-yl)-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid Example 270A (2S,3R,4S,5S)-1-allyl 2-ethyl4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-1-Allyl 2-ethyl4-hydroxy-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylatefrom Example 258D (200 mg, 0.461 mmol) and2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (166 mg, 0.646 mmol)were dissolved in dry N,N-dimethylformamide (3 mL). After cooling in anice bath, potassium 2-methylpropan-2-olate (0.646 mL, 0.646 mmol)solution was added dropwise over 4 minutes. After 30 minutes, thereaction was quenched with saturated aqueous NH₄Cl solution andextracted with dichloromethane. The organic solvent was evaporated andthe resulting residue was purified using a 24 g silica gel column with agradient of 0-70% ethyl acetate/heptanes over 20 minutes to give(2S,3R,4S,5S)-1-allyl 2-ethyl4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)pyrrolidine-1,2-dicarboxylate.¹H NMR (501 MHz, DMSO-d₆) δ ppm 7.97 (s, 1H), 7.19 (dd, J=7.9, 1.4 Hz,1H), 7.15-7.12 (m, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 7.05 (t, J=7.5 Hz,1H), 6.80 (s, 1H), 6.73 (d, J=8.6 Hz, 1H), 5.69 (d, J=154.4 Hz, 1H),5.32 (d, J=5.8 Hz, 1H), 5.21-4.80 (m, 1H), 4.59 (d, J=2.1 Hz, 1H),4.51-4.29 (m, 2H), 4.26-4.19 (m, 2H), 4.12-4.04 (m, 2H), 3.82-3.76 (m,1H), 3.61 (s, 3H), 3.33 (m, 1H), 3.19 (s, 1H), 3.16 (s, 3H), 2.76 (s,1H), 1.25 (d, J=1.4 Hz, 3H), 1.18 (d, J=4.7 Hz, 6H), 1.16 (s, 12H), 1.09(t, J=7.1 Hz, 3H); MS (APCI+) m/z 610 (M+H)⁺.

Example 270B (2S,3R,4S,5S)-ethyl4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylate

To a solution of Example 270A (150 mg, 0.246 mmol) in acetonitrile/water(4.4 mL, 10:1) was added tetrakis(triphenylphosphine)palladium(0) (6.25mg, 5.41 μmol) and diethylamine (0.051 mL, 0.492 mmol). The mixture wasstirred at ambient temperature for 2 hours. The mixture was concentratedto 1 mL, and dichloromethane and water were added. The organic layer waswashed with brine, dried over sodium sulfate, filtered, andconcentrated. The crude material was purified using a 12 g silica gelcartridge with a gradient of 0-70% ethyl acetate/heptanes over 20minutes to yield (2S,3R,4S,5S)-ethyl4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.61 (dd, J=7.9, 1.4 Hz, 1H), 7.27 (dd,J=7.8, 1.5 Hz, 1H), 7.21 (td, J=7.4, 1.5 Hz, 1H), 7.16-7.09 (m, 2H),6.79 (d, J=2.6 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 4.36 (dd, J=8.3, 4.4 Hz,1H), 4.19-4.07 (m, 3H), 3.98 (dd, J=4.5, 1.9 Hz, 1H), 3.65 (t, J=7.3 Hz,1H), 3.61 (s, 3H), 3.58 (d, J=12.0 Hz, 1H), 3.21 (p, J=6.8 Hz, 1H), 3.14(s, 3H), 3.08-3.00 (m, 1H), 2.56-2.52 (m, 1H), 1.23-1.12 (m, 24H); MS(APCI+) m/z 526 (M+H)⁺.

Example 270C (2S,3R,4S,5S)-ethyl4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of Example 270B (110 mg, 0.209 mmol) in dichloromethane(1.9 mL) at 0° C. was added triethylamine (0.131 mL, 0.942 mmol)followed by addition (S)-tetrahydro-2H-pyran-2-carbonyl chloride (52.9mg, 0.356 mmol) as a solution in 1 mL of dichloromethane. After stirringfor 15 minutes, the reaction was quenched with 5 mL of saturated aqueoussodium bicarbonate. The crude material was chromatographed using a 12 gsilica gel cartridge with a gradient of 0-65% ethyl acetate/heptanesover a period of 20 minutes to give (2S,3R,4S,5S)-ethyl4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.00 (dd, J=7.8, 1.5 Hz, 1H), 7.22 (s,1H), 7.16 (d, J=7.3 Hz, 0H), 7.09 (dd, J=8.5, 2.6 Hz, 1H), 7.04 (t,J=7.5 Hz, 1H), 6.84 (d, J=2.6 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 5.59 (s,1H), 4.76 (d, J=1.8 Hz, 1H), 4.24-4.17 (m, 2H), 4.07 (q, J=7.1 Hz, 2H),3.79 (d, J=12.4 Hz, 1H), 3.75-3.68 (m, 1H), 3.60 (s, 3H), 3.28-3.20 (m,1H), 3.18 (s, 3H), 3.12 (bs, 1H), 2.72 (s, 1H), 1.71-1.62 (m, 1H), 1.52(m, 2H), 1.36 (m, 3H), 1.30 (d, J=6.7 Hz, 3H), 1.22 (d, J=12.4 Hz, 6H),1.17 (m, 12H), 1.12 (t, J=7.1 Hz, 3H); MS (APCI+) m/z 638 (M+H)⁺.

Example 270D(2S,3R,4S,5S)-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-3-(2-methoxypropan-2-yl)-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

To a solution of Example 270C (92 mg, 0.144 mmol) in tetrahydrofuran(0.5 mL), methanol (0.500 mL) and water (0.500 mL) was added lithiumhydroxide hydrate (42.4 mg, 1.010 mmol) and the reaction was heated at45° C. for 16 hours. The solvent was removed under a stream of nitrogen.Water (1 mL) was added to the crude material. The mixture was extractedwith 5 mL heptane (discarded), and the aqueous layer was acidified with1M aqueous HCl (0.8 mL) to pH˜6, and filtered. The material waschromatographed using a 4 g silica gel cartridge with a gradient of0-10% methanol/dichloromethane over a period of 10 minutes to give(2S,3R,4S,5S)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropylphenyl)-3-(2-methoxypropan-2-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.08 (dd, J=7.9, 1.5 Hz, 1H), 7.22(d, J=7.8 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 7.09 (dd, J=8.5, 2.6 Hz, 1H),7.04 (t, J=7.6 Hz, 1H), 6.83 (d, J=2.6 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H),5.59 (s, 1H), 4.71 (d, J=1.8 Hz, 1H), 4.25-4.18 (m, 2H), 3.80 (d, J=12.6Hz, 1H), 3.74 (m, 1H), 3.61 (s, 3H), 3.28-3.20 (m, 1H), 3.18 (s, 3H),2.80-2.77 (m, 3H), 1.73-1.62 (m, 1H), 1.54 (m, 2H), 1.36 (m, 3H), 1.30(d, J=6.8 Hz, 3H), 1.21 (d, J=8.4 Hz, 6H), 1.16 (m, 12H); MS (APCI+) m/z610 (M+H)⁺.

Example 271(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid Example 271A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-1,2-dicarboxylate

The title compound was prepared according to the procedure described inExample 265A, substituting3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (Intermediate 8,342 mg, 1.266 mmol) for 3-(bromomethyl)-5-cyclobutyl-2-methoxypyridineto yield the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.28 (dq,J=2.7, 0.9 Hz, 1H), 8.08 (dd, J=7.4, 1.9 Hz, 1H), 7.88 (dd, J=5.0, 1.9Hz, 1H), 7.13-7.08 (m, 1H), 6.77 (dd, J=7.4, 4.9 Hz, 1H), 5.73 (ddt,J=17.2, 10.4, 5.1 Hz, 1H), 5.28-5.17 (m, 2H), 5.11-4.98 (m, 2H), 4.43(dt, J=5.2, 1.7 Hz, 3H), 4.37 (dt, J=13.7, 0.9 Hz, 1H), 4.29 (dd, J=6.0,1.5 Hz, 1H), 3.99 (dt, J=13.9, 0.9 Hz, 1H), 3.87 (s, 3H), 1.28 (d, J=6.1Hz, 3H), 1.20 (d, J=6.1 Hz, 3H), 1.02 (s, 9H); MS (ESI+) m/z 596.1(M+H)⁺.

Example 271B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate

The title compound was prepared according to the procedure described inExample 265B, substituting Example 271A for Example 265A to yield titlecompound. MS (APCI+) m/z 540.5 (M+H)⁺.

Example 271C(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid

To a solution of Example 271B (51.3 mg, 0.095 mmol) in toluene andsaturated aqueous sodium bicarbonate (4 mL, 1:1) was added(S)-1,1,1-trifluoropropan-2-yl carbonochloridate (16.79 mg, 0.095 mmol)dropwise at room temperature. The mixture was stirred at roomtemperature for 20 minutes. Ethyl acetate (20 mL) and water (10 mL) wereadded, and the organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified via chromatographyon a 24 g silica gel cartridge, eluting with ethyl acetate in heptane,at a 0-30% gradient to yield the ester. The ester was dissolved inmethanol (2 mL) and aqueous LiOH (0.5 mL), and stirred at 50° C. forovernight. The pH was adjusted to 0˜1 by adding 2M aqueous HCl andconcentrated to dryness. The residue was purified via chromatography ona 12 g silica gel cartridge, eluting with ethyl acetate in heptane, at0-50% gradient to provide title compound ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.36-8.27 (m, 1H), 8.08 (dd, J=7.3, 1.9 Hz, 1H), 7.91 (dd, J=5.0, 1.9Hz, 1H), 7.18-7.12 (m, 1H), 6.78 (dd, J=7.4, 4.9 Hz, 1H), 5.22 (dd,J=6.0, 2.1 Hz, 2H), 5.19-5.10 (m, 1H), 4.41 (d, J=2.3 Hz, 1H), 4.37 (d,J=13.7 Hz, 1H), 4.28 (dd, J=5.9, 1.4 Hz, 1H), 3.99 (d, J=13.8 Hz, 1H),3.87 (s, 3H), 2.53 (t, J=1.9 Hz, 1H), 1.26 (d, J=6.1 Hz, 3H), 1.20 (d,J=6.2 Hz, 3H), 1.06 (d, J=6.6 Hz, 3H), 1.01 (s, 9H); MS (ESI+) m/z 652.1(M+H)⁺.

Example 272(2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 272A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((R)-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

A mixture of Example 249D ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)allyl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(120 mg, 0.190 mmol) and 10% Pd/C (25 mg, 0.023 mmol) in ethanol (2 mL)was stirred under an atmosphere of H₂ (balloon) for 90 minutes. Themixture was diluted with ethyl acetate (25 mL), stirred for 5 minutes,and filtered to remove the solids. The filtrate was concentrated todryness. A portion of the crude product was chromatographed on silicagel, eluting with a gradient of 15% to 100% methyl tert-butyl ether inheptane to provide the title compound as the first isomer to elute fromthe column. LC/MS (ESI+) m/z 634 (M+H)⁺.

Example 272B(2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 272A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((R)-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(41.6 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was diluted withmethanol (0.5 mL), diluted with water (1 mL), treated with lithiumhydroxide hydrate (33 mg, 0.786 mmol), stirred at 45° C. overnight,heated overnight to 55° C., cooled, treated with 1 M aqueous HCl (3 mL)and extracted with ethyl acetate (50 mL). The ethyl acetate layer waswashed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 15% to 50%[200:1:1 ethyl acetate:HCOOH:H₂O] in heptane to provide the titlecompound. ¹H NMR (400 MHz, DMSO, 200° C.) δ ppm 7.99-7.94 (m, 1H), 7.44(dd, J=2.4, 8.7 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.11-7.06 (m, 3H), 7.02(d, J=8.6 Hz, 1H), 5.48 (bs, 1H), 4.59 (s, 1H), 4.06 (d, J=5.9 Hz, 1H),3.80-3.75 (m, 1H), 3.78 (s, 3H), 3.19-3.13 (m, 1H), 2.98-2.84 (m, 3H),2.38 (bs, 1H), 2.33 (s, 3H), 1.72-1.26 (m, 6H), 0.98 (s, 9H), 0.92-0.86(m, 1H), 0.84 (d, J=6.6 Hz, 3H); LC/MS (ESI+) m/z 606 (M+H)⁺.

Example 273(2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 273A ethyl(2S,3R,4S,5S)-3-(tert-butyl)-4-((S)-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

The procedure for Example 272A provided the title compound as the secondisomer to elute from the column. LC/MS (ESI+) m/z 634 (M+H)⁺.

Example 273B(2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

A solution of Example 273A ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((S)-2-(2-methoxy-5-(trifluoromethyl)phenyl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate)(41.6 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was diluted withmethanol (0.5 mL), diluted with water (1 mL), treated with lithiumhydroxide hydrate (34 mg, 0.810 mmol), stirred at 45° C. overnight,heated overnight to 55° C., cooled, treated with 1 M aqueous HCl (3 mL)and extracted with ethyl acetate (50 mL). The ethyl acetate layer waswashed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 15% to 50%[200:1:1 ethyl acetate:HCOOH:H₂O] in heptane to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 7.99-7.96 (m, 1H),7.45 (dd, J=2.4, 8.6 Hz, 1H), 7.12-7.07 (m, 4H), 7.05 (d, J=8.6 Hz, 1H),5.48 (bs, 1H), 4.58 (d, J=2.3 Hz, 1H), 4.06 (d, J=5.8 Hz, 1H), 3.82 (s,3H), 3.81-3.75 (m, 1H), 3.23 (dd, J=5.4, 9.0 Hz, 1H), 3.05-2.72 (m, 3H),2.36 (s, 3H), 2.36-2.35 (m, 1H), 1.71-1.27 (m, 6H), 0.98 (s, 9H),0.92-0.81 (m, 1H), 0.78 (d, J=6.9 Hz, 3H); LC/MS (ESI+) m/z 606 (M+H)⁺.

Example 274(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 266A and 266B, substituting (S)-1,1,1-trifluoropropan-2-ol for(R)-1,1,1-trifluoropropan-2-ol, and Intermediate 6 for Intermediate 4,respectively, to provide title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.14 (dd, J=7.4, 2.0 Hz, 1H), 7.97 (dd, J=4.9, 2.0 Hz, 1H), 7.15 (dd,J=8.6, 2.6 Hz, 1H), 6.89-6.81 (m, 2H), 6.77 (d, J=8.5 Hz, 1H), 5.36-5.27(m, 1H), 5.27-5.23 (m, 1H), 5.15 (hept, J=6.7 Hz, 1H), 4.40 (d, J=2.4Hz, 1H), 4.30 (d, J=12.4 Hz, 1H), 4.25 (dd, J=5.9, 1.5 Hz, 1H), 3.99 (d,J=12.4 Hz, 1H), 3.66 (s, 3H), 2.55 (d, J=2.0 Hz, 1H), 1.31 (d, J=6.1 Hz,3H), 1.29 (d, J=6.1 Hz, 3H), 1.20 (s, 9H), 1.08 (d, J=6.7 Hz, 3H), 1.01(s, 9H); MS (ESI+) m/z 639.2 (M+H)⁺.

Example 275(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopropane-1-carbonyl]pyrrolidine-2-carboxylicacid

To a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid[277756-46-4] (58.6 mg, 0.380 mmol) and one drop ofN,N-dimethylformamide in dichloromethane (2 mL) at −10° C. was addedoxalyl dichloride (72.4 mg, 0.571 mmol) dropwise. The mixture wasstirred at room temperature for 2 hours and was added dropwise to(2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-cyclobutyl-2-methoxypyridin-3-yl)methoxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate(Example 133G, 100 mg, 0.190 mmol) in toluene and saturated aqueoussodium bicarbonate (4 mL, 1:1) at room temperature. The mixture wasstirred for 20 minutes. Ethyl acetate (20 mL) and water (10 mL) wereadded, and the organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was dissolved in methanol (2 mL)and 6N aqueous LiOH (0.5 mL) and stirred at 50° C. for 4 hours. The pHwas adjusted to 1˜2 by adding 2M aqueous HCl, and the mixture wasconcentrated. The residue was purified via chromatography on a 10 gsilica gel cartridge, eluting with ethyl acetate/methanol (9:1) inheptane at a 0-50% gradient to provide the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.02-7.92 (m, 3H), 7.63 (d, J=2.4 Hz, 1H), 6.71 (dd,J=7.4, 4.9 Hz, 1H), 5.50 (d, J=6.5 Hz, 1H), 5.31 (hept, J=6.2 Hz, 1H),5.17 (d, J=3.1 Hz, 2H), 4.67 (d, J=4.4 Hz, 1H), 4.44 (dd, J=6.6, 3.9 Hz,1H), 3.92 (s, 3H), 3.51 (p, J=8.5 Hz, 1H), 2.38-2.28 (m, 3H), 2.14-1.82(m, 4H), 1.35 (d, J=6.1 Hz, 3H), 1.33 (d, J=6.1 Hz, 3H), 1.30-1.25 (m,1H), 1.15-1.05 (m, 2H), 1.01 (s, 9H), 0.78 (dtd, J=10.1, 5.2, 4.3, 2.7Hz, 1H); MS (ESI+) m/z 634.3 (M+H)⁺.

Example 276(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopentane-1-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 275, substituting 1-(trifluoromethyl)cyclopentanecarboxylic acid[CAS#277756-44-2] for 1-(trifluoromethyl)cyclopropanecarboxylic acid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.21 (dd, J=7.3, 1.9 Hz, 1H), 7.97 (dd,J=4.9, 2.0 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 6.89-6.82 (m, 2H), 5.58 (d,J=6.4 Hz, 1H), 5.24 (p, J=6.0 Hz, 1H), 4.72 (d, J=3.0 Hz, 1H), 4.39 (d,J=13.2 Hz, 1H), 4.25 (dd, J=6.4, 2.4 Hz, 1H), 4.09 (d, J=13.2 Hz, 1H),3.81 (s, 3H), 3.36 (q, J=8.5 Hz, 1H), 2.57 (d, J=2.7 Hz, 1H), 2.45 (t,J=7.4 Hz, 1H), 2.29-2.19 (m, 3H), 2.10-1.84 (m, 6H), 1.68 (dq, J=34.4,7.3 Hz, 3H), 1.50 (dq, J=13.6, 7.5 Hz, 1H), 1.33 (d, J=6.1 Hz, 3H), 1.29(s, 1H), 1.22 (d, J=6.1 Hz, 3H), 1.03 (s, 9H), 0.88 (d, J=7.6 Hz, 1H);MS (ESI+) m/z 662.2 (M+H)⁺.

Example 277(2S,3R,4S,5S)-3-tert-butyl-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid Example 277A (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-phenyl-4-(prop-2-yn-1-yloxy)pyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-2-Ethyl 1-isopropyl3-(tert-butyl)-4-hydroxy-5-phenylpyrrolidine-1,2-dicarboxylate fromExample 38C (49 mg, 0.130 mmol) and propargyl bromide (34.7 mg, 0.234mmol) were dissolved in dry N,N-dimethylformamide (0.5 mL). Aftercooling in an ice bath, potassium 2-methylpropan-2-olate (0.208 mL,0.208 mmol) (1M in tetrahydrofuran) was added dropwise over 2 minutes.After 15 minutes, the mixture was acidified with 1M aqueous HCl (10drops) and warmed to ambient temperature. The mixture was concentratedand loaded onto a 12 g silica gel column and was eluted with 5-100%methyl tert-butyl ether/heptanes over 20 minutes to give(2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-5-phenyl-4-(prop-2-yn-1-yloxy)pyrrolidine-1,2-dicarboxylate.MS (APCI+) m/z 415 (M+H)⁺.

Example 277B (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylate

(2S,3R,4S,5S)-2-Ethyl 1-isopropyl3-(tert-butyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylatefrom Example 277A (58 mg, 0.098 mmol),3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (30.5 mg, 0.119 mmol),copper(I) iodide (2.063 mg, 10.83 μmol) andtetrakis(triphenylphosphine)palladium(0) (12.51 mg, 10.83 μmol) werecombined under nitrogen with nitrogen sparged toluene (289 μL) andtriethylamine (144 μL). The resulting solution was heated to 60° C. for3.5 hours. The solvent was removed under a stream of nitrogen. Diethylether was added, leaving behind a precipitate (PPh₃O), which wasfiltered out. The filtrate was purified using a 10 g silica gelcartridge eluting with 0-20% ethyl acetate/heptanes over 20 minutes togive (2S,3R,4S,5S)-2-ethyl 1-isopropyl3-(tert-butyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylate.MS (APCI+) m/z 591 (M+H)⁺.

Example 277C(2S,3R,4S,5S)-3-tert-butyl-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid

(2S,3R,4S,5S)-2-Ethyl 1-isopropyl3-(tert-butyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-5-phenylpyrrolidine-1,2-dicarboxylatefrom Example 277B (58 mg, 0.098 mmol) and lithium hydroxide (20 mg,0.835 mmol) were combined in methanol (0.3 mL), water (0.300 mL) andtetrahydrofuran (0.3 mL). The resulting solution was heated to 50° C.for 17 hours. The solvent was removed under a stream of nitrogen and thecrude material was acidified with 2N aqueous HCl (0.42 mL). The crudematerial was purified using a 10 g silica gel cartridge eluting with anethyl acetate/ethanol/heptanes solvent system to give(2S,3R,4S,5S)-3-(tert-butyl)-1-(isopropoxycarbonyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-5-phenylpyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (dd, J=2.4, 1.2 Hz, 1H), 7.90(d, J=2.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.26-7.13 (m, 3H), 4.98 (d, J=6.4Hz, 1H), 4.62 (p, J=6.2 Hz, 1H), 4.38 (dd, J=6.5, 3.0 Hz, 1H), 4.26 (d,J=3.6 Hz, 1H), 3.99 (s, 3H), 3.95 (d, J=16.7 Hz, 1H), 3.82 (d, J=16.7Hz, 1H), 1.05 (d, J=6.2 Hz, 3H), 1.02 (s, 10H), 0.88 (d, J=6.2 Hz, 3H);MS (APCI+) m/z 563 (M+H)⁺.

Example 278(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 278A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitro-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitropyrrolidine-2-carboxylate (Core24B) (500 mg, 1.435 mmol) in dichloromethane (5 mL) at 0° C. was addedtriethylamine (0.900 mL, 6.46 mmol) followed by addition(S)-tetrahydro-2H-pyran-2-carbonyl chloride (362 mg, 2.436 mmol) as asolution in 2 mL dichloromethane. After stirring for 15 minutes, themixture was quenched with 5 mL of saturated aqueous sodium bicarbonateand the crude material was chromatographed using a 24 g silica gelcartridge with a gradient of 0-80% ethyl acetate/heptanes over a periodof 20 minutes to give (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitro-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31 (d, J=2.1 Hz, 1H), 7.73 (s, 1H),7.55 (d, J=7.5 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.20 (d, J=17.6 Hz, 2H),5.40 (s, 1H), 4.63 (s, 1H), 4.38-4.24 (m, 2H), 4.10 (qd, J=7.1, 3.9 Hz,2H), 3.91 (d, J=13.7 Hz, 1H), 3.88 (s, 3H), 3.78 (d, J=11.3 Hz, 1H),3.49 (bs, 1H), 3.10 (bs, 1H), 2.39 (t, J=2.3 Hz, 1H), 1.68 (m, 1H), 1.51(m, 2H), 1.39 (m, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.00 (s, 9H); MS (APCI+)m/z 461 (M+H)⁺.

Example 278B (2S,3R,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-oxo-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

In a 100 mL flask was charged DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)(0.743 mL, 4.93 mmol) and carbon disulfide (0.425 mL, 7.05 mmol) in 1.4mL CH₃CN and the mixture was stirred at ambient temperature for 30minutes. To the mixture at 0° C. was added (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-nitro-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 278A (649 mg, 1.409 mmol) in 1.4 mL of CH₃CN. The mixturewas allowed to warm to room temperature for 2 hours. CH₃CN (28 mL) wasadded and 7.4 mL of 10% H₃PO₄ solution was added to hydrolyze theresulting imine in 2 hours at ambient temperature. Methyl tert-butylether (10 mL) and 6 mL brine were added, and the organic layer waswashed with 18 mL of brine with the addition of 18 mL methyl tert-butylether. The organics were filtered and concentrated. The hydrolysis wasrepeated by stirring the crude material for 5 hours in 24 mL CH₃CN and10 mL 10% H₃PO₄. Methyl tert-butyl ether (10 mL) and 6 mL brine wereadded and the organic layer was washed with 18 mL of brine with theaddition of 18 mL methyl tert-butyl ether. The mixture was filtered andconcentrated, and the residue was chromatographed using a 24 g silicagel cartridge with a gradient of 0-60% ethyl acetate/heptanes over aperiod of 20 minutes to give (2S,3R,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-oxo-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.82 (dd, J=7.8, 1.4 Hz, 1H), 7.24 (dt,J=14.6, 7.5 Hz, 2H), 7.18-7.08 (m, 1H), 5.58 (s, 1H), 4.73 (d, J=4.4 Hz,1H), 4.20 (qd, J=7.1, 5.0 Hz, 2H), 3.74 (dtd, J=11.4, 3.8, 1.4 Hz, 1H),3.22-2.99 (m, 2H), 2.81-2.70 (m, 2H), 2.50 (d, J=4.4 Hz, 1H), 1.82-1.61(m, 1H), 1.50 (m, 2H), 1.37 (m, 3H), 1.28-1.18 (m, 6H), 1.04 (s, 9H); MS(APCI+) m/z 430 (M+H)⁺.

Example 278C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,5S)-Ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-oxo-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 278B (11.48 g, 26.7 mmol) was heated to dissolve in ethanol(200 mL). Sodium borohydride (2.022 g, 53.5 mmol) was added aftercooling the reaction to <−10° C. in an ice/acetone bath. The ice bathwas removed after 5 minutes and the reaction was allowed to warm to roomtemperature over 40 minutes. The mixture was concentrated and theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. After 1.5 hours, the organics were concentrated andthe crude material was purified via flash chromatography, eluting with0-100% ethyl acetate/heptanes over a period of 20 minutes on a 80 gsilica gel cartridge to give (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.95 (d, J=7.6 Hz, 1H), 7.22-7.15 (m,2H), 7.13 (m, 1H), 5.46 (s, 1H), 4.46 (s, 1H), 4.41-4.32 (m, 1H), 4.16(q, J=7.1 Hz, 2H), 3.83 (bs, 1H), 3.75 (dd, J=11.4, 3.9 Hz, 1H), 3.43(bs, 1H), 3.02 (bs, 1H) 2.71 (ddt, J=19.7, 14.7, 7.4 Hz, 2H), 2.22 (t,J=3.5 Hz, 1H), 1.64 (m, 1H), 1.47 (m, 2H), 1.35 (m, 3H), 1.25 (td,J=7.3, 1.8 Hz, 6H), 0.99 (s, 9H); MS (APCI+) m/z 432 (M+H)⁺.

Example 278D (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-(prop-2-yn-1-yloxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

To a cooled solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 278C (324 mg, 0.751 mmol) in N,N-dimethylformamide (1.5 mL)was added potassium 2-methylpropan-2-olate, 1M in tetrahydrofuran (0.901mL, 0.901 mmol) followed by propargyl bromide (134 mg, 0.901 mmol)dropwise over 2 minutes. After 15 minutes, the mixture was acidifiedwith 1M aqueous HCl (20 drops) and warmed to ambient temperature. Themixture was diluted with methyl tert-butyl ether and water. The mixturewas separated and the organics were washed with water and brine,concentrated and loaded onto a 10 g silica gel cartridge. The cartridgewas eluted with 5-100% ethyl acetate/heptanes over 20 minutes to give(2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-(prop-2-yn-1-yloxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.93 (dd, J=7.6, 1.1 Hz, 1H), 7.17 (d,J=4.3 Hz, 2H), 7.15-7.06 (m, 1H), 5.48 (s, 1H), 4.61 (d, J=2.0 Hz, 1H),4.29 (d, J=5.8 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.71 (dd, J=11.4, 4.0Hz, 1H), 3.58 (dd, J=16.2, 2.3 Hz, 1H), 3.42 (dd, J=16.2, 2.4 Hz, 1H),2.96 (t, J=2.4 Hz, 1H), 2.73 (qd, J=7.5, 5.6 Hz, 2H), 2.36 (d, J=1.9 Hz,1H), 1.71-1.60 (m, 1H), 1.57-1.42 (m, 1H), 1.41-1.29 (m, 3H), 1.25 (dt,J=13.3, 7.3 Hz, 7H), 1.01 (s, 11H); MS (APCI+) m/z 470 (M+H)⁺.

Example 278E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-(prop-2-yn-1-yloxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 278D (100 mg, 0.213 mmol) and3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (36.0 μL, 0.234 mmol),copper(I) iodide (4.06 mg, 0.021 mmol) andtetrakis(triphenylphosphine)palladium(0) (24.61 mg, 0.021 mmol) werecombined under nitrogen with nitrogen sparged toluene (568 μL) andtriethylamine (284 μL). The resulting solution was heated to 50° C. for17 hours. The solvent was removed under a stream of nitrogen and thecrude material was added to diethyl ether, leaving behind a precipitate(PPh₃O). After filtration, the solid was rinsed with additional diethylether and the combined ether washes were purified using a 10 g silicagel cartridge eluting with 0-20% ethyl acetate/heptanes over 20 minutesto give (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (dd, J=2.4, 1.2 Hz, 1H), 7.96 (dd,J=7.4, 1.3 Hz, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.21-7.07 (m, 3H), 5.52 (s,1H), 4.64 (d, J=1.9 Hz, 1H), 4.43 (d, J=5.8 Hz, 1H), 4.16 (qd, J=7.1,1.8 Hz, 2H), 3.99 (s, 3H), 3.92 (d, J=16.7 Hz, 1H), 3.71 (d, J=16.7 Hz,1H), 2.78-2.65 (m, 2H), 2.42 (d, J=1.9 Hz, 1H), 1.70-1.59 (m, 2H),1.57-1.42 (m, 2H), 1.33 (tt, J=7.7, 4.2 Hz, 5H), 1.23 (td, J=7.3, 1.4Hz, 6H), 1.03 (s, 9H); MS (APCI+) m/z 645 (M+H)⁺.

Example 278F(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-ethylphenyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid

(2S,3R,4S,5S)-Ethyl3-(tert-butyl)-5-(2-ethylphenyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylatefrom Example 278E (91 mg, 0.141 mmol) and lithium hydroxide (31 mg,1.294 mmol) were combined in methanol (0.5 mL), water (0.500 mL) andtetrahydrofuran (0.5 mL). The resulting solution was heated to 50° C.for 17 hours. The solvent was removed under a stream of nitrogen and wasacidified with 2N aqueous HCl (0.65 mL). The crude material was purifiedusing a 10 g silica gel cartridge eluting with an ethylacetate/ethanol/heptanes solvent system to give(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-ethylphenyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (dd, J=2.4, 1.2 Hz, 1H), 8.02(d, J=7.7 Hz, 1H), 7.87 (d, J=2.6 Hz, 1H), 7.22-7.08 (m, 3H), 5.53 (s,1H), 4.60 (d, J=1.8 Hz, 1H), 4.45 (d, J=5.9 Hz, 1H), 3.99 (s, 3H), 3.94(d, J=16.8 Hz, 1H), 3.78-3.66 (m, 3H), 2.83-2.65 (m, 3H), 2.48 (d, J=1.8Hz, 2H), 1.65 (d, J=13.1 Hz, 1H), 1.50 (t, J=11.1 Hz, 1H), 1.33 (ddd,J=22.4, 11.7, 5.3 Hz, 4H), 1.23 (t, J=7.6 Hz, 3H), 1.03 (s, 9H); MS(APCI+) m/z 617 (M+H)⁺.

Example 279(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-4-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methoxy}pyrrolidine-2-carboxylicacid Example 279A 1-(allyloxy)-2-iodo-4-(trifluoromethyl)benzene

A solution of 2-iodo-4-(trifluoromethyl)phenol (2.28 g, 7.92 mmol) inN,N-dimethylformamide (60 mL) was treated with K₂CO₃ (3.61 g, 26.1mmol), treated with allyl bromide (2.261 mL, 26.1 mmol) and stirred atroom temperature for 3 hours. The mixture was diluted with methyltert-butyl ether (50 mL) and filtered to remove the solids. The filtratewas diluted with methyl tert-butyl ether (100 mL) and heptanes (150 mL).The mixture was washed with water (twice, 500 mL and 100 mL). Theorganic layer was washed with brine, dried (MgSO₄), filtered, andconcentrated to provide the title compound,1-(allyloxy)-2-iodo-4-(trifluoromethyl)benzene. ¹H NMR (400 MHz, CDCl₃)δ ppm 8.03 (d, J=2.2 Hz, 1H), 7.55 (dd, J=2.2, 8.7 Hz, 1H), 6.84 (d,J=8.6 Hz, 1H), 6.05 (ddt, J=4.8, 10.6, 17.3 Hz, 1H), 5.53 (dq, J=1.5,17.3 Hz, 1H), 5.37-5.33 (m, 1H), 4.66 (dt, J=1.6, 4.7 Hz, 2H).

Example 279B 3-methyl-5-(trifluoromethyl)benzofuran

A solution of Example 279A(1-(allyloxy)-2-iodo-4-(trifluoromethyl)benzene) (2.38 g, 7.25 mmol) inN,N-dimethylformamide (22 mL) was treated with sodium formate (0.523 g,7.69 mmol), tetrabutylammonium chloride (2.480 g, 8.92 mmol), Na₂CO₃(2.307 g, 21.76 mmol) and palladium(II) acetate (0.212 g, 0.943 mmol)and was stirred at 85° C. for 2 hours and then stirred overnight at roomtemperature. The mixture was diluted with methyl tert-butyl ether (50mL) and the resulting solids were removed by filtration and discarded.The filtrate was diluted with additional methyl tert-butyl ether (100mL) and heptanes (150 mL), and washed with water (twice, 500 mL and 100mL). The organic layer was washed with brine, dried (MgSO₄), filtered,concentrated, and chromatographed on silica gel, eluting with pentane toprovide the title compound, 3-methyl-5-(trifluoromethyl)benzofuran. ¹HNMR (501 MHz, CDCl₃) δ ppm 7.83-7.81 (m, 1H), 7.55 (dd, J=1.8, 8.6 Hz,1H), 7.52 (dt, J=0.7, 8.6 Hz, 1H), 7.50 (q, J=1.3 Hz, 1H), 2.28 (d,J=1.4 Hz, 3H).

Example 279C 3-(bromomethyl)-5-(trifluoromethyl)benzofuran

A solution of Example 279B (3-methyl-5-(trifluoromethyl)benzofuran) (95mg, 0.475 mmol) and benzoyl peroxide (28.7 mg, 0.119 mmol) inchlorobenzene (2 mL) was heated to 120° C. and was treated withN-bromosuccinimide (84 mg, 0.475 mmol) in 4 portions in 10 minuteintervals. The mixture was heated a further 2 hours at 120° C. and wascooled. The mixture was diluted with pentane (˜30 mL). The solid wasremoved by filtration and was discarded. The filtrate was concentratedand chromatographed on silica gel, eluting with pentane to provide thetitle compound, 3-(bromomethyl)-5-(trifluoromethyl)benzofuran. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.00 (d, J=0.9 Hz, 1H), 7.80 (s, 1H), 7.64-7.57(m, 2H), 4.63 (d, J=0.8 Hz, 2H).

Example 279D ethyl(2S,3R,4S,5S)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-52824-((5-(trifluoromethyl)benzofuran-3-yl)methoxy)pyrrolidine-2-carboxylate

Example 169B ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate)(28 mg, 0.061 mmol) was dissolved in toluene (˜2 mL) and the resultingsolution was concentrated. The residue was treated with Example 279C(3-(bromomethyl)-5-(trifluoromethyl)benzofuran) (22.05 mg, 0.079 mmol).The mixture was dissolved in N,N-dimethylformamide (0.5 mL) under N₂,cooled to −30° C., treated with 1 M potassium tert-butoxide intetrahydrofuran (72.9 μL, 0.073 mmol), stirred at −20° C. for −15minutes, quenched with 1 M aqueous HCl (3 mL) and partitioned betweenwater (5 mL) and ethyl acetate (50 mL). The ethyl acetate layer waswashed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 15% to 100%ethyl acetate in heptane to provide the title compound,(2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-isopropoxypyridin-3-yl)-4-((5-(trifluoromethyl)benzofuran-3-yl)methoxy)pyrrolidine-2-carboxylate.LC/MS (ESI+) m/z 659 (M+H)⁺.

Example 279E(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-4-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methoxy}pyrrolidine-2-carboxylicacid

A solution of Example 279D ((2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-isopropoxypyridin-3-yl)-4-((5-(trifluoromethyl)benzofuran-3-yl)methoxy)pyrrolidine-2-carboxylate)(30 mg, 0.046 mmol) in tetrahydrofuran (1 mL) was diluted with methanol(0.5 mL), diluted with water (1 mL), treated with lithium hydroxidehydrate (38.2 mg, 0.911 mmol), heated to 55° C. for 4 hours, heated to60° C. for 1 hour, and heated to 65° C. for 30 minutes. The mixture wascooled, acidified with 1 M aqueous HCl (4 mL) and extracted with ethylacetate (30 mL). The ethyl acetate layer was washed with brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 15% to 100% [200:1:1 ethyl acetate:HCOOH:H₂O]in heptane to provide the title compound,(2S,3R,4S,5S)-3-(tert-butyl)-1-(cyclohexanecarbonyl)-5-(2-isopropoxypyridin-3-yl)-4-((5-(trifluoromethyl)benzofuran-3-yl)methoxy)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.19 (bs, 1H), 7.97-7.93(m, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.52 (s, 2H),6.86-6.81 (m, 1H), 5.36 (bs, 1H), 5.27-5.17 (m, 1H), 4.56 (d, J=2.6 Hz,1H), 4.48 (dd, J=1.0, 12.6 Hz, 1H), 4.32-4.25 (m, 2H), 2.56 (bs, 1H),1.72-1.06 (m, 10H), 1.32 (d, J=5.9 Hz, 3H), 1.21 (d, J=6.2 Hz, 3H), 1.00(s, 9H), 0.91-0.83 (m, 1H); LC/MS (APCI+) m/z 631 (M+H)⁺.

Example 280(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]propoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

(2S,3R,4S,5S)-3-(tert-Butyl)-5-(2-ethylphenyl)-4-((3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid from Example 278F (36 mg, 0.058 mmol) in tetrahydrofuran (1.0 mL)was added to 5% Pd/C (wet JM#9) (12.4 mg, 0.052 mmol) in a 20 mLBarnstead reactor. The reactor was purged with argon. The mixture wasstirred at 1200 RPM under 50 psi of hydrogen at 25° C. for 17 hours. Themixture was filtered through a polypropylene membrane and the solventwas removed in vacuo to give(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-ethylphenyl)-4-(3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.30 (d, J=2.3 Hz, 1H), 8.00 (d,J=7.5 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.11 (s, 3H), 5.52 (s, 1H), 4.57(s, 1H), 3.97 (q, J=5.3, 4.9 Hz, 1H), 3.90 (s, 3H), 3.79-3.66 (m, 1H),3.36-3.20 (m, 1H), 3.15-3.07 (m, 2H), 2.72-2.59 (m, 2H), 2.34 (s, 1H),2.23-2.09 (m, 3H), 1.71-1.55 (m, 1H), 1.55-1.40 (m, 1H), 1.35 (s, 5H),1.22 (t, J=7.5 Hz, 4H), 0.97 (s, 9H); MS (APCI+) m/z 621 (M+H)⁺.

Example 281(2S,3R,4S,5S)-3-tert-butyl-5-(5-iodo-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 141 (207 mg, 0.358 mmol) was dissolved in dichloromethane (3.6mL) and I₂ (100 mg, 0.394 mmol) and silver(I) trifluoromethanesulfonate(193 mg, 0.751 mmol) were added. The reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was diluted withCH₂Cl₂ (10 mL) and stirred with saturated aqueous sodium thiosulfate (10mL) for 10 minutes. After the red color disappeared, the mixture wasfiltered through a fritted funnel and the layers were separated. Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo. The crude material was separated via reverse-phase HPLC on aPhenomenex® C8(2) Luna® 5 μm AXIA™ 150×30 mm column using an aqueoustrifluoroacetic acid (0.1%):CH₃CN mobile phase to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.42 (d, J=1.9 Hz, 1H), 8.31(dd, J=2.6, 1.1 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H),6.88 (d, J=8.0 Hz, 1H), 5.46 (s, 1H), 4.67 (s, 1H), 4.41-4.22 (m, 2H),3.89 (m, 1H), 3.89 (s, 3H), 3.82-3.74 (m, 1H), 3.20 (m, 1H), 2.44-2.39(m, 1H), 2.28 (s, 3H), 1.70 (dt, J=13.2, 4.2 Hz, 1H), 1.57 (d, J=12.4Hz, 1H), 1.41 (dd, J=19.2, 9.4 Hz, 5H), 1.02 (s, 9H); MS (ESI) m/z 705.0(M+H)⁺.

Example 282(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1R,2R)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylicacid Example 282A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((1R,2R)-2-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylate and (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((1S,2S)-2-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylate

To 2-(trifluoromethyl)cyclohexanecarboxylic acid [CAS#384-20-3](160 mg,0.815 mmol) in dichloromethane (2 mL) and one drop ofN,N-dimethylformamide was added oxalyl dichloride (155 mg, 1.223 mmol,0.62 mL, 2 M in dichloromethane) dropwise. The mixture was stirred atroom temperature for 20 minutes, concentrated, and dissolved indichloromethane (1 mL). The mixture was added to the solution of(2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)pyrrolidine-2-carboxylate(Example 271A, 220 mg, 0.408 mmol) in toluene (3 mL) and saturatedaqueous NaHCO₃ (3 mL). The mixture was stirred at room temperature for20 minutes. Dichloromethane (20 mL) and water (10 mL) were added and theorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification via chromatography on a 24 g silica gelcartridge, eluting with ethyl acetate in heptane using a 0-40% gradientto provide the first eluent, arbitrarily assigned as (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((1R,2R)-2-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylate. MS (APCI) m/z 718.6 (M+H)⁺; and the secondeluent was arbitrarily assigned as (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((1S,2S)-2-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylate. MS (APCI+) m/z 718.6 (M+H)⁺.

Example 282B(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((1R,2R)-2-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylicacid

To (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((1R,2R)-2-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylate (first eluent from Example 282A, 100 mg, 0.139mmol) was added methanol (2 mL) and 6N aqueous LiOH (0.5 mL). Themixture was stirred at room temperature overnight. The pH was adjustedto 1˜2 by adding 2N aqueous HCl and the precipitate was filtered, washedwith water, and dried in vacuo to provide(2S,3R,4S,5S)-3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((1R,2R)-2-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylic acid as a trifluoroacetic acid salt. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.41 (d, J=7.3 Hz, 1H), 8.33 (s, 1H), 7.98 (d,J=4.4 Hz, 1H), 7.15 (s, 1H), 6.88 (s, 1H), 5.57 (d, J=6.5 Hz, 1H), 5.25(s, 1H), 4.46 (d, J=4.1 Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.26 (dd,J=6.6, 2.8 Hz, 1H), 4.00 (d, J=13.8 Hz, 1H), 3.88 (s, 3H), 3.19 (s, 1H),2.66 (s, 1H), 2.43 (s, 1H), 2.21 (d, J=27.6 Hz, 2H), 1.68 (d, J=12.5 Hz,2H), 1.50 (s, 1H), 1.26 (d, J=6.4 Hz, 3H), 1.21 (d, J=6.5 Hz, 3H), 1.16(s, 2H), 1.00 (s, 9H), 0.87 (d, J=25.9 Hz, 2H); MS (ESI+) m/z 690.2(M+H)⁺.

Example 283(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1S,2S)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 282B, substituting the second eluent from Example 282A for thefirst eluent from Example 282A, to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.30 (d, J=1.8 Hz, 2H), 7.89 (s, 1H), 7.10 (s,1H), 6.75 (s, 1H), 5.35 (s, 1H), 5.24 (h, J=6.3 Hz, 1H), 4.55 (d, J=2.9Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.29 (d, J=6.0 Hz, 1H), 4.04 (d,J=20.9 Hz, 1H), 3.89 (s, 3H), 2.55 (s, 2H), 1.75-1.33 (m, 6H), 1.31 (d,J=6.2 Hz, 3H), 1.27 (d, J=5.0 Hz, 1H), 1.21 (d, J=6.1 Hz, 3H), 1.02 (s,9H); MS (ESI+) m/z 690.1 (M+H)⁺.

Example 284(2S,3R,4S,5S)-3-tert-butyl-4-{2-[(5-chloro-2-methoxypyridin-3-yl)oxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid Example 284A (2S,3R,4S,5S)-ethyl4-(2-(tert-butoxy)-2-oxoethoxy)-3-(tert-butyl)-1-(tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

A solution of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-hydroxy-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 188B, 505 mg, 1.209 mmol) and tert-butyl bromoacetate (894 μL,6.05 mmol) in N,N-dimethylformamide (6 mL) was cooled to −40 C, treateddropwise with 1 M potassium tert-butoxide in tetrahydrofuran (2419 μL,2.419 mmol), stirred at −40° C. for 5 minutes, and warmed to −20° C. Themixture was treated with additional 1 M potassium tert-butoxide intetrahydrofuran (1209 μL, 1.209 mmol), stirred for 5 minutes, warmed to−15 C, treated with more 1 M potassium tert-butoxide in tetrahydrofuran(1209 μL, 1.209 mmol), stirred for 5 minutes, and quenched withsaturated aqueous NH₄Cl solution (5 mL). The mixture was partitionedbetween methyl tert-butyl ether (75 mL) and water (75 mL). The layerswere separated and the aqueous layer was extracted with methyltert-butyl ether (50 mL). The combined methyl tert-butyl ether layerswere washed with brine, dried (MgSO4), filtered, concentrated andchromatographed on an Analogix IntelliFlash 280 using a 25 g columneluting with 10% (1 minutes), 10 to 30% (over 14 minutes) ethyl acetatein heptane to provide the title compound. MS (APCI+) m/z 532 (M+H)⁺.

Example 284B2-(((2S,3S,4R,5S)-4-(tert-butyl)-5-(ethoxycarbonyl)-1-(tetrahydro-2H-pyran-2-carbonyl)-2-(o-tolyl)pyrrolidin-3-yl)oxy)aceticacid

A solution of (2S,3R,4S,5S)-ethyl4-(2-(tert-butoxy)-2-oxoethoxy)-3-(tert-butyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate(Example 284A, 472 mg, 0.888 mmol) in trifluoroacetic acid (3 mL) washeated to 55° C. for 2 minutes. The reaction mixture was concentratedand dried under vacuum overnight at 50° C. to provide the titlecompound,2-(((2S,3S,4R,5S)-4-(tert-butyl)-5-(ethoxycarbonyl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-2-(o-tolyl)pyrrolidin-3-yl)oxy)aceticacid. MS (APCI+) m/z 476 (M+H)⁺.

Example 284C (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-(2-hydroxyethoxy)-1-(tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate

To a solution of2-(((2S,3S,4R,5S)-4-(tert-butyl)-5-(ethoxycarbonyl)-1-(tetrahydro-2H-pyran-2-carbonyl)-2-(o-tolyl)pyrrolidin-3-yl)oxy)aceticacid (Example 284B, 360 mg, 0.757 mmol) in tetrahydrofuran (1 mL) at−10° C. was added 4-methylmorpholine (0.092 mL, 0.833 mmol), andisobutyl carbonochloridate (0.107 mL, 0.833 mmol). The mixture wasstirred for 30 minutes and added to a solution of sodium borohydride(57.3 mg, 1.514 mmol) in H₂O (0.200 mL) at 0° C. After 30 minutes, themixture was quenched via addition of saturated aqueous NH₄Cl anddichloromethane (230 mL). The organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified viachromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptane, at 0-40% gradient to yield (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-(2-hydroxyethoxy)-1-(tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate.MS (APCI+) m/z 462.4 (M+H)⁺.

Example 284D(2S,3R,4S,5S)-3-tert-butyl-4-{2-[(5-chloro-2-methoxypyridin-3-yl)oxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

To a mixture of Example 284C (80 mg, 0.173 mmol) and5-chloro-2-methoxypyridin-3-ol [cas 1261365-86-9] (27.7 mg, 0.173 mmol)in tetrahydrofuran (1 mL) was added triphenylphosphine (68.2 mg, 0.260mmol), and (E)-di-tert-butyl diazene-1,2-dicarboxylate (59.9 mg, 0.260mmol) portionwise. After 30 minutes, the mixture was quenched viaaddition of saturated aqueous NH₄Cl (5 mL) and dichloromethane (20 mL).The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography on a 24 gsilica gel cartridge, eluting with ethyl acetate in heptane, at 0-40%gradient to yield (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-(2-((5-chloro-2-methoxypyridin-3-yl)oxy)ethoxy)-1-(tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylate.The ester was dissolved in methanol (2 mL) and 6M aqueous LiOH (0.5 mL),and the mixture was stirred at 50° C. for 4 hours. The pH was adjustedto 0˜1 by adding 2M aqueous HCl. The mixture was concentrated to drynessand was purified via HPLC with trifluoroacetic acid method to yield(2S,3R,4S,5S)-3-(tert-butyl)-4-(2-((5-chloro-2-methoxypyridin-3-yl)oxy)ethoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.00-7.94 (m, 1H), 7.67 (d, J=2.3Hz, 1H), 7.07 (d, J=2.8 Hz, 3H), 7.02 (d, J=2.2 Hz, 1H), 5.47 (s, 1H),4.60-4.51 (m, 1H), 4.25 (dd, J=5.9, 1.3 Hz, 1H), 3.85 (s, 3H), 3.79-3.73(m, 1H), 3.73-3.68 (m, 1H), 3.62 (ddd, J=11.0, 5.8, 3.8 Hz, 1H), 3.42(m, 1H), 3.29 (ddd, J=11.8, 6.2, 4.0 Hz, 1H), 3.05 (ddd, J=11.8, 5.8,3.9 Hz, 2H), 2.40 (d, J=2.2 Hz, 1H), 2.34 (s, 3H), 1.70-1.60 (m, 1H),1.51 (q, J=11.8, 10.5 Hz, 1H), 1.43-1.06 (m, 4H), 1.00 (s, 9H); MS(ESI+) m/z 575.2 (M+H)⁺.

Example 285(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 285A (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-nitropyrrolidine-1,2-dicarboxylate

To a mixture of (2S,3R,4S,5S)-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-nitropyrrolidine-2-carboxylate(Core 7, 10.237 g, 27.0 mmol) in toluene (100 mL) and saturated aqueousNaHCO₃ (50 mL) was added allyl carbonochloridate (3.0 mL, 28.2 mmol)dropwise at room temperature. The mixture was stirred for 30 minutes.Methyl tert-butyl ether (400 mL) was added and the organic layer waswashed sequentially with 1M aqueous HCl, 1M aqueous NaOH, and brine,dried over MgSO₄, filtered, and concentrated to dryness to provide thetitle compound, which used in next step without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.00 (dd, J=4.9, 1.9 Hz, 1H), 7.96 (ddd,J=7.4, 1.9, 0.8 Hz, 1H), 6.85 (dd, J=7.4, 5.0 Hz, 1H), 5.80-5.66 (m,1H), 5.53 (d, J=8.3 Hz, 1H), 5.42 (dd, J=8.3, 2.8 Hz, 1H), 5.28 (dt,J=12.4, 6.1 Hz, 1H), 5.08 (t, J=1.6 Hz, 1H), 5.05 (dq, J=6.9, 1.6 Hz,1H), 4.58 (d, J=3.5 Hz, 1H), 4.46 (ddt, J=4.2, 3.1, 1.6 Hz, 2H),4.28-4.19 (m, 2H), 2.96 (ddd, J=3.6, 2.8, 0.7 Hz, 1H), 2.46 (p, J=1.9Hz, 1H), 1.32 (dd, J=6.8, 6.2 Hz, 6H), 1.27 (t, J=7.1 Hz, 2H), 1.01 (s,9H); MS (APCI+) m/z 464 (M+H)⁺.

Example 285B (2S,3R,5S)-1-allyl 2-ethyl3-(tert-butyl)-5-(2-isopropoxypyridin-3-yl)-4-oxopyrrolidine-1,2-dicarboxylate

A 500 mL flask was charged DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)(14.64 mL, 97 mmol) and CS₂ (8.36 mL, 139 mmol) in (55.5 mL). Themixture was stirred at room temperature for 1 hour and was cooled downto 0° C. Example 285A (12.86 g, 27.7 mmol) in acetonitrile (5 mL) wasadded. After the addition, the mixture allowed to room temperature andwas stirred for 2 hours. Ethyl acetate (200 mL) and 100 mL brine wereadded to the mixture, and the organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated. CH₃CN (100 mL) and 20% H₃PO₄(100 mL) solution were added to hydrolyze the resulted imine at roomtemperature for 4 hours. Ethyl acetate (200 mL) and brine (100 mL) wereadded to the reaction mixture. The organic layer was washed with 80 mLof brine, dried over Na₂SO₄, filtered and concentrated. Purification viachromatography using a 220 g silica gel cartridge, eluting with agradient of 0-30% ethyl acetate in heptane provided the title compound.HPLC 97.8 PA % at 11.45 minute; MS (APCI+) m/z 444 (M+H)⁺.

Example 285C (2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-hydroxy-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

To Example 285B (10.33 g, 23.88 mmol) in ethanol (119 mL) cooled to<−10° C. in a brine-ice bath was added sodium borohydride (0.994 g, 26.3mmol) in one portion. After the addition, the temperature was allowed towarm to room temperature and the mixture was stirred for 40 minutes. Thereaction was quenched by adding acetone (20 mL) slowly over 10 minutes.The mixture was concentrated under pressure and the residue waspartitioned between saturated aqueous sodium bicarbonate and methyltert-butyl ether. The organic layer was washed with 1M aqueous HCl andbrine, dried over sodium sulfate, filtered, and concentrated.Purification of the residue via chromatography on a 80 g silica gelcartridge, eluting with ethyl acetate in heptane at 0-30% gradient toprovide the title compound. MS (APCI+) m/z 435.5 (M+H)⁺.

Example 285D 2S,3R,4S,5S)-1-allyl 2-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

To Example 285C (500 mg, 1.151 mmol) and2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (Intermediate 6, 355 mg,1.381 mmol) in N,N-dimethylformamide (5 mL) cooling in an ice bath,potassium 2-methylpropan-2-olate (1.83 mL, 1.0 M in tetrahydrofuran) wasadded dropwise. The mixture was stirred in ice bath for 20 minutes, andallowed to warm to ambient temperature. Ethyl acetate (30 mL) and water(10 mL) were added. The organic layer was washed with brine, dried overMgSO₄, filtered, and concentrated to provide the title compound, whichused in next step without further purification. MS (APCI+) m/z 611(M+H)⁺.

Example 285E (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropoxypyridin-3-yl)pyrrolidine-2-carboxylate

To a solution of 285D (700 mg, 1.146 mmol) and1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (358 mg, 2.292 mmol) inethyl acetate/dichloromethane (10 mL, 1:1) was added Pd(Ph₃)₄(tetrakis(triphenylphosphine)palladium(0), 23.65 mg, 0.023 mmol). Themixture was stirred at room temperature for 20 minutes. Dichloromethane(20 mL) and water (10 mL) were added, and the organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified via chromatography on a 24 g silica gel cartridge, elutingwith ethyl acetate in heptane at 0-40% gradient to provide the titlecompound. MS (APCI+) m/z 527.6 (M+H)⁺.

Example 285F(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxy-phenyl)methoxy]-5-(2-isopropoxy-3-pyridyl)-1-[(2S)-tetrahydropyran-2-carbonyl]pyrrolidine-2-carboxylicacid

To (S)-tetrahydro-2H-pyran-2-carboxylic acid (29.7 mg, 0.228 mmol) indichloromethane (2 mL) and one drop of N,N-dimethylformamide was addedoxalyl dichloride (38.6 mg, 0.304 mmol) dropwise. The mixture wasstirred at room temperature for 20 minutes, and the solvent wasevaporated under reduced pressure. The residue was dissolved indichloromethane (1 mL) and added to a solution of Example 285E (80 mg,0.152 mmol) in a mixture of toluene and saturated aqueous NaHCO₃ (6 mL,1:1) at room temperature. The mixture was stirred at room temperaturefor 20 minutes. Ethyl acetate (20 mL) and water (10 mL) were added andthe organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography on a 14 gsilica gel cartridge, eluting with ethyl acetate in heptane, at 0-40%gradient to provide (2S,3R,4S,5S)-ethyl3-(tert-butyl)-4-((5-(tert-butyl)-2-methoxybenzyl)oxy)-5-(2-isopropoxypyridin-3-yl)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate,which dissolved in methanol (2 mL) and 6N aqueous LiOH (0.5 mL). Themixture was stirred at 50° C. overnight. The pH of the reaction mixturewas adjusted to 0˜1 by adding 2N aqueous HCl and the mixture wasconcentrated. The residue was purified via a 24 g silica gel cartridge,eluting with ethyl acetate/methanol in heptane to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.21 (s, 1H), 7.96 (s, 1H),7.11 (dd, J=8.5, 2.6 Hz, 1H), 6.83 (d, J=2.7 Hz, 2H), 6.74 (d, J=8.5 Hz,1H), 5.61 (s, 1H), 5.29 (p, J=6.1 Hz, 1H), 4.60 (s, 1H), 4.29 (d, J=12.4Hz, 1H), 4.21 (dd, J=6.2, 1.9 Hz, 1H), 3.96 (d, J=12.4 Hz, 1H),3.83-3.75 (m, 1H), 3.63 (s, 3H), 3.44 (d, J=10.8 Hz, 1H), 2.45 (d, J=2.3Hz, 1H), 1.69 (d, J=12.7 Hz, 1H), 1.54 (s, 1H), 1.38 (s, 2H), 1.34 (d,J=6.2 Hz, 3H), 1.29 (s, 1H), 1.26 (d, J=6.1 Hz, 3H), 1.17 (s, 9H),1.13-1.00 (m, 1H), 0.97 (s, 9H), 0.90-0.79 (m, 1H); MS (ESI+) m/z 611.4(M+H)⁺.

Example 286(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(²H₃)methylphenyl]-1-[(2S,3S)-(2,3-²H₂)oxane-2-carbonyl](2-²H)pyrrolidine-2-carboxylicacid Example 286A (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-((2S,3S)-2,3-d₂-tetrahydro-2H-pyran-2-carbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(2-bromo-phenyl)pyrrolidine-2-carboxylate

Argon-degassed 3% triethylamine-d₁₅ in CH₃OD (20 mL) was added to3,4-dihydro-2H-pyran-6-carboxylic acid (0.976 g, 7.62 mmol), anddiacetato[(S)-(−)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II)(0.134 g, 0.161 mmol) under argon in a 50 mL SS reactor. The mixture wasstirred at room temperature under argon. The vessel was vented,pressurized with 50 psi deuterium, and stirred at 60° C. under 120 psiof deuterium for 22 hours. The solvent was removed in vacuo and theresidue was taken up in CH₂Cl₂ (20 mL), washed with D₂O (3×5 mL), driedover sodium sulfate, filtered, and concentrated in vacuo. The crudematerial was dissolved in 21 mL of CH₂Cl₂ and the solution was treatedwith oxalyl chloride (0.93 mL, 10.6 mmol, 2 eq) andN,N-dimethylformamide (0.020 mL, 0.05 eq). The reaction mixture wasstirred at room temperature for 1 hour and the volatile material wasremoved in vacuo. The resulting material was azeotroped with 2×10 mL ofCH₂Cl₂ to give the crude acid chloride, which was used immediatelywithout additional purification. In a separate round-bottomed flask,Example 178B (1.25 g, 2.234 mmol) was dissolved in 10 mL ofdichloromethane. The resulting solution was cooled to <5° C. in an icewater bath, and triethylamine (0.779 mL, 5.59 mmol) was added, followedby dropwise addition of the freshly-prepared solution of the acidchloride in dichloromethane (7 mL). After five minutes, 1M aqueous HCl(10 mL) was added and the biphasic mixture was stirred for 5 minutes atroom temperature. The layers were separated. The organic layer waswashed with aqueous 1M HCl (2×10 mL) and aqueous 1M NaOH (10 mL) thenbrine (10 mL), dried over sodium sulfate, filtered, and concentrated invacuo to give a crude mixture of diastereomers in approximately a 7:1ratio, which was purified via flash chromatography, eluting with 0:100to 10:90 methyl tert-butyl ether:heptanes over 20 minutes on a 120 gsilica gel column to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆, 120° C.) δ ppm 8.30 (d, J=2.1 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H),7.50 (d, J=7.9 Hz, 1H), 7.25 (s, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.12 (s,1H), 4.74 (s, 1H), 4.39 (d, J=5.9 Hz, 1H), 4.33 (d, J=13.6 Hz, 1H), 4.10(qd, J=7.1, 2.2 Hz, 2H), 3.95 (d, J=13.7 Hz, 1H), 3.88 (s, 3H),3.82-3.75 (m, 1H), 2.44 (t, J=1.3 Hz, 1H), 1.68 (d, J=12.9 Hz, 1H), 1.45(d, J=50.4 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.03 (s, 9H); MS (ESI) m/z673.0 (M+H)⁺.

Example 286B (2S,3R,4S,5S)-ethyl3-(tert-butyl)-1-((2S,3S)-2,3-d₂-tetrahydro-2H-pyran-2-carbonyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-5-(2-(d₃-methyl)phenyl)pyrrolidine-2-carboxylate

1,2-Dioxane (17 mL) and D₂O (4.3 mL) were degassed with a stream of N₂for 120 minutes. Example 286A (725 mg, 1.076 mmol), cesium carbonate(1.4 g, 4.3 mmol), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (440 mg, 0.538 mmol) were weighed into a 30 mLscintillation vial, and the vial was purged with N₂ for 20 minutes. Thesolvents were added to the vial, followed by methyl-d₃-boronic acid(0.53 mL, 3.23 mmol) and the reaction mixture was sealed and heated to95° C. in a preheated heating block. After 2 hours, the vial was cooledto room temperature, opened, and sampled on LC-MS, which showed completeconversion of the starting material. The reaction mixture was dilutedwith methyl tert-butyl ether (50 mL) and washed with 10 mL of D₂O. Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was purified via flash chromatography, eluting onan 80 g silica gel column with 0:100 to 20:80 methyl tert-butylether:heptanes over 25 minutes to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆, 120° C.) δ ppm 8.34-8.25 (m, 1H), 8.05-7.93 (m, 1H),7.28-7.17 (m, 1H), 7.08 (d, J=8.2 Hz, 3H), 5.56 (s, 1H), 4.69 (s, 1H),4.33-4.23 (m, 2H), 4.10 (qd, J=7.1, 2.7 Hz, 2H), 3.87 (s, 3H), 3.81 (s,1H), 3.80-3.72 (m, 1H), 2.44-2.39 (m, 1H), 1.66 (d, J=12.7 Hz, 1H), 1.49(d, J=11.3 Hz, 1H), 1.34 (t, J=27.6 Hz, 4H), 1.15 (t, J=7.1 Hz, 3H),1.03 (s, 9H); MS (ESI) m/z 612.1 (M+H)⁺.

Example 286C2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(²H₃)methylphenyl]-1-[(2S,3S)-(2,3-²H₂)oxane-2-carbonyl](2-²H)pyrrolidine-2-carboxylicacid

Example 286B (315 mg, 0.515 mmol) was dissolved in 1.5 mL of CD₃OD.Sodium hydroxide (103 mg, 2.57 mmol), was added, and the resultingsuspension was heated to 50° C. for 4 hours. The solution was cooled toroom temperature, washed with heptanes (2×1 mL) and was diluted with D₂O(0.5 mL). The resulting sodium salt of the title compound was extractedinto methyl tert-butyl ether (3×5 mL). The combined organic extractswere concentrated in vacuo and the residue was redissolved in ethylacetate and 5 mL of water and 3 mL of HCl were added to give a solutionof pH=2. The desired product was extracted into ethyl acetate (3×5 mL),and the combined extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo to provide the title compound. (Deuterium exchangeof the ester methine proton occurred during the reaction conditions). ¹HNMR (400 MHz, DMSO-d₆, 120° C.) δ ppm 8.28 (dd, J=2.5, 1.1 Hz, 1H),8.10-7.94 (m, 1H), 7.22-7.16 (m, 1H), 7.15-7.00 (m, 3H), 5.56 (s, 1H),4.34-4.25 (m, 2H), 3.88 (s, 3H), 3.85 (s, 1H), 3.75 (s, 1H), 2.44-2.39(m, 1H), 1.72-1.61 (m, 1H), 1.51 (d, J=11.7 Hz, 1H), 1.45-1.21 (m, 4H),1.03 (s, 9H); MS (ESI) m/z 585.2 (M+H)⁺.

Example 287(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

Example 169B (60 mg, 0.13 mmol) was dissolved into anhydrous toluene,dried over NaSO₄, filtered, and concentrated. The residue was placedunder nitrogen, a solution of Example 243D (38 mg, 0.15 mmol) inanhydrous N,N-dimethylformamide (400 μL) was added, and the mixture wascooled to −40° C. Potassium tert-butoxide in tetrahydrofuran (1 M, 0.14mL, 0.14 mmol) was added dropwise over eight minutes, and the reactionmixture was stirred for 15 minutes near −40° C. The mixture was allowedto warm to −5° C. over an hour before being quenched with 3 M aqueouscitric acid (30 μL). Brine was added, the reaction mixture was extractedthrice with methyl tert-butyl ether and the combined organic phases weredried (Na₂SO₄), filtered, and concentrated. The residue was diluted withmethanol (900 μL), treated with 1.5 M aqueous NaOH (1.2 mL) and heatedat 55° C. for 24 hours. Methanol (900 μL), tetrahydrofuran (900 μL) and1.5 M aqueous LiOH (600 μL) were added and the reaction mixture washeated at 65° C. overnight. Additional tetrahydrofuran (1.8 mL) and 1.5M aqueous LiOH (1.2 mL) were added and the reaction mixture was stirredat room temperature over the weekend. NaOH (50% aqueous 200 μL) wasadded and the reaction mixture was heated at 55° C. overnight. Thereaction mixture was brought to room temperature, concentrated, dilutedwith methyl tert-butyl ether, acidified with 1 M aqueous citric acid andstirred well. The aqueous phase was separated and extracted with methyltert-butyl ether and the combined organic phases were concentrated andchromatographed on silica (20 to 50% methyl tert-butyl ether in 1:3CH₂Cl₂/heptane) to provide the title compound. MS (ESI+) m/z 608 (M+H)⁺.

Example 288(2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenoxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 284D, substituting 2-methoxy-5-(trifluoromethyl)phenol [cas349-67-7] for 5-chloro-2-methoxypyridin-3-ol. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.97 (dd, J=5.9, 2.9 Hz, 1H), 7.22 (ddq, J=8.4, 1.7, 0.8 Hz, 1H),7.07 (d, J=8.4 Hz, 4H), 6.92 (d, J=2.2 Hz, 1H), 5.48 (s, 1H), 4.56 (d,J=2.3 Hz, 1H), 4.27 (dd, J=5.9, 1.3 Hz, 1H), 3.80 (s, 3H), 3.76 (d,J=11.3 Hz, 1H), 3.69 (ddd, J=10.5, 6.1, 4.2 Hz, 1H), 3.60 (ddd, J=10.6,5.7, 4.2 Hz, 1H), 3.39 (s, 1H), 3.32-3.26 (m, 1H), 3.09-3.04 (m, 2H),2.41 (d, J=1.9 Hz, 1H), 2.34 (s, 3H), 1.70-1.59 (m, 1H), 1.61-1.45 (m,1H), 1.45-1.19 (m, 3H), 1.12 (d, J=30.1 Hz, 1H), 1.00 (s, 9H); MS (ESI+)m/z 608.2 (M+H)⁺.

Example 289(2S,3R,4S,5S)-4-[(5-bromo-1-benzofuran-2-yl)methoxy]-3-tert-butyl-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 285D to Example 285F, substituting 5-bromo-2-(bromomethyl)benzofuran [CAS#84102-72-7] for(2-(bromomethyl)-4-(tert-butyl)-1-methoxybenzene (Intermediate 6). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.20 (s, 1H), 8.04 (d, J=4.7 Hz, 1H), 7.71(dd, J=1.8, 0.9 Hz, 1H), 7.38-7.36 (m, 2H), 6.90 (t, J=6.1 Hz, 1H), 6.39(d, J=0.9 Hz, 1H), 5.63 (s, 1H), 5.26 (hept, J=6.0 Hz, 1H), 4.63 (s,1H), 4.35-4.24 (m, 2H), 4.18 (dd, J=13.7, 0.8 Hz, 1H), 3.80 (d, J=11.4Hz, 1H), 3.58 (s, 2H), 2.46 (d, J=2.4 Hz, 1H), 1.76-1.36 (m, 5H), 1.35(d, J=6.1 Hz, 3H), 1.25-1.22 (m, 3H), 1.22-1.12 (m, 1H), 0.99 (s, 9H);MS (ESI+) m/z 643.1 (M+H)⁺.

Example 290(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid Example 290A 3-(bromomethyl)-6-(tert-butyl)-2-methoxypyridine

To triphenylphosphine (2.216 g, 8.45 mmol) in dichloromethane (10 mL)cooling in an ice bath was added 1-bromopyrrolidine-2,5-dione (1.504 g,8.45 mmol) portionwise. The mixture was stirred for 30 minutes,maintaining an internal temperature<10° C., and(6-(tert-butyl)-2-methoxypyridin-3-yl) methanol (1.1 g, 5.63 mmol) indichloromethane (10 mL) was added in portions at <10° C. The mixture wasstirred in ice bath for 1 hour and was allowed to warm to ambienttemperature. The mixture was stirred overnight. Saturated aqueous NH₄Cl(2 mL) was added and the mixture was washed with saturated aqueoussodium bicarbonate. The organic layer was dried over MgSO₄, filtered,and concentrated. Purification via chromatography on 24 g silica gelcartridge, eluting with ethyl acetate in heptane at 0-30% gradientprovided the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.51(dd, J=7.6, 1.4 Hz, 1H), 6.84 (dd, J=7.7, 1.5 Hz, 1H), 4.49 (d, J=1.5Hz, 2H), 4.00 (d, J=1.5 Hz, 3H), 1.32 (d, J=1.5 Hz, 9H); MS (ESI+) m/z258.0 (M+H)⁺.

Example 290B(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedures described inExample 285C to Example 285F, substituting Example 290A for Intermediate6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.16 (s, 1H), 7.98 (s, 1H), 6.86 (t,J=6.8 Hz, 2H), 6.70 (d, J=7.6 Hz, 1H), 5.60 (s, 1H), 5.25 (p, J=6.1 Hz,1H), 4.63 (s, 1H), 4.23-4.17 (m, 2H), 3.95 (dd, J=13.1, 0.9 Hz, 1H),3.79 (s, 3H), 3.77 (s, 1H), 3.59-3.44 (m, 2H), 3.47 (d, J=109.1 Hz, 2H),2.43 (d, J=2.1 Hz, 1H), 1.70 (d, J=12.5 Hz, 1H), 1.63-1.35 (m, 4H), 1.33(d, J=6.0 Hz, 3H), 1.30 (d, J=1.1 Hz, 1H), 1.25 (s, 9H), 1.23 (d, J=6.1Hz, 3H), 0.98 (s, 9H); MS (ESI+) m/z 612.2 (M+H)⁺.

Example 291(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedures described inExample 285C to Example 285F, substituting Example 290A for Intermediate6, and cyclohexanecarbonyl chloride for(S)-tetrahydro-2H-pyran-2-carboxylic acid, respectively. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.16 (s, 1H), 7.98 (s, 1H), 6.86 (t, J=8.9 Hz, 2H),6.70 (d, J=7.6 Hz, 1H), 5.33 (s, 1H), 5.27 (p, J=6.1 Hz, 1H), 4.52 (d,J=2.7 Hz, 1H), 4.24-4.15 (m, 2H), 3.97 (d, J=13.0 Hz, 1H), 3.79 (s, 3H),2.3-2.15 (m, 2H), 1.67 (d, J=9.3 Hz, 2H), 1.52 (s, 2H), 1.32 (d, J=6.1Hz, 3H), 1.25 (s, 12H), 1.11 (d, J=14.6 Hz, 3H), 0.98 (s, 9H), 0.91-0.77(m, 2H); MS (ESI+) m/z 610 (M+H)⁺.

Example 292(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]-4-{[7-(trifluoromethyl)-1-benzofuran-2-yl]methoxy}pyrrolidine-2-carboxylicacid

Into a 4 mL vial was weighed Example 278D (30 mg, 0.064 mmol, 1.0 eq),tetrakis(triphenylphosphine)palladium(0) (7.38 mg, 0.0064 mmol, 0.10 eq)and CuI (1.2 mg, 0.0064 mmol, 0.10 eq). N,N-dimethylformamide (500 μL)was added, followed by neat 2-iodo-6-(trifluoromethyl)phenol (20.2 mg,0.070 mmol, 1.1 eq), and neat trimethylamine (90 μL, 0.64 mmol, 10 eq).The reaction was stirred overnight at 60° C. The crude material waspurified via preparative reverse phase HPLC/MS method trifluoroaceticacid 8 and carried forward without further characterization. Thematerial was dissolved in 500 μL 3:2 tetrahydrofuran/methanol. LiOHmonohydrate (5 M in water, 100 L) was added and the reaction was stirredovernight at 50° C. The solvent was removed under a stream of nitrogen.The residue was acidified with 2 M aqueous HCl and extracted withdichloromethane (3×1 mL). The solvent was removed under a stream ofnitrogen, and the residue was dissolved in CH₃CN and purified usingpreparative reverse phase HPLC/MS method trifluoroacetic acid 8. ¹H NMR(400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.02 (dd, J=7.7, 1.5 Hz,1H), 7.80 (d, J=7.8 Hz, 1H), 7.54 (dt, J=7.7, 1.0 Hz, 1H), 7.37 (tt,J=7.8, 0.9 Hz, 1H), 7.24-7.09 (m, 3H), 6.53-6.47 (m, 1H), 5.54-5.49 (m,1H), 4.63 (d, J=1.9 Hz, 1H), 4.28 (d, J=5.7 Hz, 1H), 4.12-3.98 (m, 2H),3.74 (d, J=11.4 Hz, 1H), 3.61-3.33 (m, 1H), 3.08-2.87 (m, 1H), 2.80-2.52(m, 2H), 2.46 (d, J=1.9 Hz, 1H), 1.71-1.59 (m, 1H), 1.56-1.45 (m, 1H),1.42-1.26 (m, 3H), 1.22-1.02 (m, 4H), 0.97 (s, 9H); MS (APCI+) m/z 602.0(M+H)⁺.

Example 293(2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-1-benzofuran-2-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid

Example 293 was prepared following the general procedure used to prepareExample 292, substituting 2-iodo-4-chlorophenol for2-iodo-6-(trifluoromethyl)phenol. ¹H NMR (400 MHz, 120° C.,DMSO-d₆:D₂O=9:1 (v/v)) δ ppm 8.00 (dd, J=7.7, 1.4 Hz, 1H), 7.52 (d,J=2.2 Hz, 1H), 7.42-7.35 (m, 1H), 7.27-7.08 (m, 4H), 6.36-6.32 (m, 1H),5.59-5.41 (m, 1H), 4.63 (d, J=1.9 Hz, 1H), 4.22 (d, J=5.6 Hz, 1H), 4.06(d, J=13.9 Hz, 1H), 3.96 (d, J=13.9 Hz, 1H), 3.78-3.67 (m, 1H),3.61-3.29 (m, 1H), 2.97 (s, 1H), 2.78-2.55 (m, 2H), 2.46-2.41 (m, 1H),1.72-1.59 (m, 1H), 1.58-1.45 (m, 1H), 1.44-1.23 (m, 3H), 1.23-1.01 (m,4H), 0.98 (s, 9H); MS (APCI+) m/z 568.0 (M+H)⁺.

Example 294(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(naphthalene-1-sulfonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described into Example 265C, substituting naphthalene-1-sulfonyl chloride [cas85-46-1] for 1,1,1-trifluoropropan-2-yl carbonochloridate to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.74 (dt, J=7.6, 1.4 Hz,1H), 8.12 (dt, J=8.2, 1.2 Hz, 1H), 8.05 (dd, J=7.4, 1.3 Hz, 1H),8.00-7.94 (m, 1H), 7.92 (dd, J=7.4, 2.0 Hz, 1H), 7.81-7.73 (m, 2H),7.64-7.53 (m, 2H), 7.50 (dd, J=8.2, 7.4 Hz, 1H), 6.86-6.81 (m, 1H), 6.39(dd, J=7.4, 4.9 Hz, 1H), 5.37 (d, J=6.7 Hz, 1H), 5.22-5.10 (m, 1H), 4.40(dd, J=5.2, 1.0 Hz, 1H), 4.15 (d, J=12.8 Hz, 1H), 3.95 (dd, J=6.7, 4.0Hz, 1H), 3.87 (d, J=12.9 Hz, 1H), 3.71 (d, J=0.7 Hz, 3H), 3.34-3.26 (p,J=8.4 Hz, 1H), 2.40 (d, J=4.2 Hz, 1H), 2.27-2.14 (m, 2H), 1.98-1.77 (m,4H), 1.32 (d, J=6.1 Hz, 3H), 1.18 (dd, J=6.2, 1.0 Hz, 3H), 0.79 (d,J=0.9 Hz, 9H); MS (ESI+) m/z 688 (M+H)⁺.

Example 295(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure described inExample 285C to Example 285F, substituting Example 96B for Example 285B,and cyclohexanecarbonyl chloride for(S)-tetrahydro-2H-pyran-2-carboxylic acid, respectively. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.06 (d, J=7.8 Hz, 1H), 7.78 (dd, J=2.3, 0.8 Hz,1H), 7.32-7.25 (m, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H),6.87 (d, J=2.4 Hz, 1H), 5.41 (d, J=5.9 Hz, 1H), 4.65 (d, J=1.8 Hz, 1H),4.28-4.20 (m, 2H), 3.83 (dt, J=13.4, 0.9 Hz, 1H), 3.78 (s, 3H),3.38-3.25 (m, 3H), 2.57 (s, 1H), 2.30-2.22 (m, 2H), 2.03-1.85 (m, 4H),1.72-1.40 (m, 5H), 1.32 (d, J=6.7 Hz, 3H), 1.28 (d, J=9.8 Hz, 3H), 1.20(d, J=6.8 Hz, 3H), 1.09 (t, J=7.0 Hz, 2H), 1.05 (s, 9H); MS (ESI+) m/z591 (M+H)⁺.

Example 296(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-1-benzofuran-2-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid

Into a 4 mL vial was added Example 289 (13 mg, 0.020 mmol) and PEPPSIIPentCl (1.737 mg, 2.020 μmol) in tetrahydrofuran (0.5 mL).Cyclobutylzinc(II) bromide (0.202 mL, 0.101 mmol) was added. Thereaction was stirred at room temperature for 3 hours. The solvent wasremoved under a stream of nitrogen. The residue was dissolved in 1 mLdichloromethane, and 1 mL 2M HCl was added. The aqueous layer wasextracted with dichloromethane (2×1 mL). The solvent was removed under astream of nitrogen. The residue was reconstituted in CH₃CN and purifiedusing reverse phase HPLC/MS method trifluoroacetic acid 8 to provide thetitle compound. ¹H NMR (400 MHz, 120° C., DMSO-d₆:D₂O=9:1 (v/v)) δ ppm8.23-8.04 (m, 1H), 8.04-7.94 (m, 1H), 7.34-7.26 (m, 1H), 7.24 (d, J=8.4Hz, 1H), 7.07 (dd, J=8.5, 1.9 Hz, 1H), 6.91-6.77 (m, 1H), 6.28 (s, 1H),5.28-5.10 (m, 1H), 4.58 (s, 1H), 4.26-4.17 (m, 2H), 4.09 (d, J=13.4 Hz,1H), 3.75 (d, J=12.1 Hz, 1H), 3.62-3.47 (m, 1H), 2.40 (s, 1H), 2.37-2.26(m, 2H), 2.13-1.89 (m, 3H), 1.88-0.99 (m, 16H), 0.93 (s, 9H); MS (APCI+)m/z 619.1 (M+H)⁺.

Determination of Biological Activity Cell Surface Expression-HorseRadish Peroxidase (CSE-HRP) Assay

A cellular assay for measuring the F508delCFTR cell surface expressionafter correction with test compounds either without or with aco-corrector (2 μM of3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoicacid), was developed in human lung derived epithelial cell line(CFBE4lo−) (Veit G et al, (2012) Mol Biol Cell. 23(21): 4188-4202). Thedevelopment was achieved by expressing the F508delCFTR mutation alongwith a horseradish peroxidase (HRP) in the fourth exofacial loop, andthen measuring the HRP activity using luminescence readout from thesecells, CFBE4lo-F508delCFTR-HRP, that were incubated overnight with thetest corrector compounds, either without or with the co-corrector. Forthis primary assay, the CFBE4lo-F508delCFTR-HRP cells were plated in384-well plates (Greiner Bio-one; Cat 781080) at 4,000 cells/well alongwith 0.5 μg/mL doxycycline to induce the F508delCFTR-HRP expression andfurther incubated at 37° C., 5% CO₂ for 72 hours. The test compoundswere then added either without or with a co-corrector at the requiredconcentrations and further incubated for 18-24 hours at 33° C. Thehighest concentration tested was 20 μM with an 8-point concentrationresponse curve using a 3-fold dilution in both the test compound withoutor with the co-corrector. Three replicate plates were run to determineone EC₅₀. All plates contained negative controls (dimethyl sulfoxide,DMSO) and positive control (2 μM of3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoicacid) as well as on-plate concentration response of the positivecontrol. Post incubation, the plates were washed 5× times withDulbecco's phosphate buffered saline (DPBS), followed by the addition ofthe HRP substrate, luminol (50 μL), and measuring the HRP activity usingluminescence readout on EnVision® Multilabel Plate Reader (Perkin Elmer;product number 2104-0010). The raw counts from the experiment wereanalyzed using Accelrys® Assay Explorer v3.3.

Z′ greater than 0.5 was used as passing quality control criteria for theplates.

The Z′ is defined as:

1−[3*SD_(Positive Control)+3*SD_(Negative Control)/Absolute(Mean_(Positive Control)−Mean_(Negative Control))]

wherein “SD” is standard deviation.

The % activity measured at each of the 8 test concentrations of the testcompound added either without or with a co-corrector (2 μM of3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoicacid) was normalized to the on-plate positive control using thefollowing formulae:

% activity (Test compound without co-corrector)=[(test compound withoutco-corrector response−DMSO response)/(positive control response−DMSOresponse)]*100

% activity (Test compound with co-corrector)=[(test compound withco-corrector response−DMSO response)/(positive control response−DMSOresponse)]*100

The maximum % activity achieved for the test compound either without orwith a co-corrector at any tested concentration is presented in Table 1along with the respective EC₅₀'s calculated using the following generalsigmoidal curve with variable Hill slope equation (described as Model 42in the Accelrys® Assay Explorer v3.3 software):

y=(a−d)/(1+(x/c){circumflex over ( )}b)+d

General sigmoidal curve with concentration, response, top, bottom, EC₅₀and Hill slope. This model describes a sigmoidal curve with anadjustable baseline, a. The equation can be used to fit curves whereresponse is either increasing or decreasing with respect to theindependent variable, “x”.

“x” is a concentration of drug under test.“y” is the response.“a” is the maximum response, and “d” is the minimum response“c” is the inflection point (EC₅₀) for the curve. That is, “y” ishalfway between the lower and upper asymptotes when x=c.“b” is the slope-factor or Hill coefficient. The sign of b is positivewhen the response increases with increasing dose and is negative whenthe response decreases with increasing dose (inhibition).The data is presented with the qualifiers shown below:

Without/with co- corrector EC50 (μM) <1 +++  ≥1 and <10 ++ ≥10 + Withoutco- Maximum % corrector activity (%) <100 + ≥100 and <200 ++ ≥200 +++Maximum % With co-corrector activity (%) <150 + ≥150 and <350 ++ ≥350+++

TABLE 1 CSE-HRP data Maximum % Maximum % EC₅₀ (without activity EC₅₀(with activity (with co-corrector) (without co- co-corrector)co-corrector) Example (μM) corrector) (%) (μM) (%) 1 ++ + ++ +++ 2 ++ ++++ +++ 3 ++ ++ ++ +++ 4 ++ ++ ++ +++ 5 ++ ++ ++ +++ 6 ++ + ++ +++7 + + + + 8 + + + + 9 + + + + 10 ++ +++ ++ +++ 11 ++ ++ ++ +++ 12 ++ ++++ +++ 13 ++ + ++ +++ 14 ++ ++ ++ +++ 15 ++ ++ ++ +++ 16 ++ + ++ ++ 17++ ++ ++ +++ 18 + + ++ ++ 19 +++ +++ +++ +++ 20 +++ ++ +++ +++ 21 + + ++++ 22 + + + + 23 + + ++ ++ 24 + + ++ ++ 25 + + ++ ++ 26 ++ + ++ ++ 27 ++++ +++ +++ 28 ++ ++ ++ +++ 29 ++ +++ ++ +++ 30 ++ ++ +++ +++ 31 ++ ++++++ +++ 32 ++ + ++ +++ 33 ++ ++ ++ +++ 34 ++ + ++ +++ 35 ++ ++ ++ +++ 36++ ++ ++ +++ 37 ++ +++ ++ +++ 38 ++ ++ ++ +++ 39 ++ +++ ++ +++ 40 ++ ++++ +++ 41 +++ ++ +++ +++ 42 ++ + ++ +++ 43 ++ + ++ +++ 44 ++ + ++ +++ 45++ ++ ++ +++ 46 +++ +++ +++ +++ 47 ++ +++ ++ +++ 48 ++ ++ ++ +++ 49 ++++ ++ +++ 50 +++ +++ +++ +++ 51 ++ ++ ++ +++ 52 ++ + ++ +++ 53 +++ +++++ +++ 54 +++ ++ +++ +++ 55 ++ ++ ++ +++ 56 +++ ++ +++ +++ 57 ++ ++ +++++ 58 +++ ++ +++ +++ 59 ++ + ++ ++ 60 +++ ++ +++ +++ 61 +++ +++ +++ +++62 +++ ++ +++ +++ 63 ++ ++ ++ +++ 64 ++ ++ ++ +++ 65 +++ + +++ +++ 66+++ + ++ +++ 67 +++ + +++ +++ 68 +++ + ++ +++ 69 ++ + ++ ++ 70 ++ + ++++ 71 ++ + ++ +++ 72 ++ + ++ +++ 73 ++ ++ +++ +++ 74 ++ ++ ++ +++75 + + + + 76 ++ ++ ++ +++ 77 ++ ++ ++ +++ 78 ++ ++ ++ +++ 79 ++ + ++ ++80 ++ + ++ ++ 81 ++ + ++ ++ 82 ++ + ++ ++ 83 ++ ++ +++ +++ 84 ++ + ++ ++85 ++ + ++ ++ 86 ++ ++ +++ +++ 87 ++ ++ ++ +++ 88 ++ ++ +++ +++ 89 ++ +++++ +++ 90 ++ + ++ +++ 91 ++ ++ ++ +++ 92 ++ ++ ++ +++ 93 ++ ++ ++ +++94 + + +++ + 95 ++ ++ +++ +++ 96 +++ +++ +++ +++ 97 ++ ++ ++ +++ 98 +++++ +++ +++ 99 ++ ++ ++ +++ 100 ++ + ++ ++ 101 ++ ++ ++ +++ 102 ++ + ++++ 103 ++ ++ +++ +++ 104 ++ ++ ++ +++ 105 +++ ++ +++ +++ 106 ++ + ++ ++107 ++ + ++ ++ 108 ++ ++ ++ +++ 109 ++ + ++ ++ 110 ++ ++ ++ +++ 111 ++++ ++ +++ 112 ++ ++ +++ +++ 113 ++ + ++ ++ 114 + + + + 115 ++ ++ +++ +++116 ++ ++ ++ +++ 117 +++ + +++ ++ 118 ++ ++ +++ +++ 119 ++ ++ ++ +++ 120++ + +++ ++ 121 +++ + +++ ++ 122 + + + + 123 ++ ++ +++ +++ 124 ++ + +++++ 125 +++ + +++ ++ 126 + + + + 127 + + + + 128 ++ ++ +++ +++ 129 ++ +++++ +++ 130 +++ ++ +++ +++ 131 +++ + +++ ++ 132 ++ ++ +++ +++ 133 ++ ++++ +++ 134 ++ ++ ++ ++ 135 ++ ++ +++ +++ 136 +++ ++ +++ +++ 137 ++ +++++ ++ 138 +++ ++ +++ +++ 139 ++ ++ +++ +++ 140 +++ + +++ ++ 141 ++ ++++++ +++ 142 +++ + +++ ++ 143 ++ ++ ++ +++ 144 +++ ++ +++ +++ 145 ++ + +++++ 146 ++ + +++ ++ 147 ++ ++ +++ +++ 148 + + + + 149 ++ ++ +++ +++ 150++ ++ +++ +++ 151 +++ + +++ ++ 152 +++ + ++ ++ 153 +++ + +++ ++ 154+++ + +++ ++ 155 ++ ++ +++ +++ 156 ++ ++ +++ +++ 157 +++ + +++ ++ 158+++ ++ +++ +++ 159 +++ + +++ +++ 160 ++ + ++ ++ 161 ++ + ++ +++ 162 +++++ +++ +++ 163 + + + + 164 + + + + 165 ++ ++ ++ +++ 166 ++ + ++ +++ 167++ + ++ ++ 168 ++ ++ ++ +++ 169 ++ +++ ++ +++ 170 ++ +++ +++ +++ 171 +++++ ++ +++ 172 ++ +++ ++ +++ 173 ++ +++ ++ +++ 174 +++ +++ +++ +++ 175++ +++ +++ +++ 176 ++ +++ +++ +++ 177 ++ ++ ++ +++ 178 ++ ++ ++ +++ 179+++ +++ +++ +++ 180 +++ +++ +++ +++ 181 + + ++ ++ 182 ++ +++ +++ +++ 183++ ++ ++ +++ 184 +++ +++ +++ +++ 185 ++ +++ +++ +++ 186 ++ +++ +++ +++187 ++ +++ +++ +++ 188 +++ +++ +++ +++ 189 ++ +++ ++ +++ 190 ++ +++ +++++ 191 ++ +++ ++ +++ 192 ++ + ++ ++ 193 ++ ++ ++ +++ 194 ++ +++ +++ +++195 ++ +++ ++ +++ 196 ++ ++ ++ +++ 197 ++ + ++ ++ 198 ++ +++ ++ +++ 199++ +++ ++ +++ 200 ++ +++ +++ +++ 201 ++ +++ ++ +++ 202 ++ +++ ++ +++ 203++ +++ ++ +++ 204 ++ +++ +++ +++ 205 ++ ++ ++ +++ 206 ++ +++ ++ +++ 207++ ++ ++ +++ 208 ++ +++ ++ +++ 209 ++ ++ ++ +++ 210 +++ ++ +++ +++ 211++ +++ +++ +++ 212 ++ ++ ++ +++ 213 ++ +++ +++ +++ 214 ++ + ++ ++ 215+++ +++ +++ +++ 216 ++ + +++ +++ 217 ++ +++ +++ +++ 218 +++ +++ +++ +++219 +++ +++ +++ +++ 220 ++ ++ +++ +++ 221 ++ +++ ++ +++ 222 ++ +++ ++++++ 223 ++ +++ +++ +++ 224 +++ +++ +++ +++ 225 ++ + ++ ++ 226 +++ ++++++ +++ 227 ++ +++ +++ +++ 228 ++ +++ +++ +++ 229 ++ + +++ ++ 230 ++ +++++ +++ 231 ++ +++ +++ +++ 232 ++ +++ +++ +++ 233 ++ +++ +++ +++ 234 ++++++ +++ +++ 235 +++ +++ +++ +++ 236 ++ ++ ++ +++ 237 ++ +++ +++ +++ 238++ +++ +++ +++ 239 ++ ++ +++ +++ 240 ++ ++ +++ +++ 241 ++ +++ +++ +++242 ++ ++ ++ +++ 243 ++ +++ +++ +++ 244 ++ ++ ++ +++ 245 ++ +++ ++ +++246 ++ +++ +++ +++ 247 ++ +++ ++ +++ 248 ++ +++ ++ +++ 249 ++ +++ ++++++ 250 +++ ++ +++ +++ 251 +++ +++ +++ +++ 252 ++ +++ ++ +++ 253 ++ +++++ +++ 254 ++ +++ +++ +++ 255 + + ++ ++ 256 ++ + +++ +++ 257 +++ + +++++ 258 +++ +++ +++ +++ 259 +++ +++ +++ +++ 260 +++ +++ +++ +++ 261 +++++ +++ +++ 262 ++ + ++ ++ 263 + + ++ ++ 264 ++ + ++ +++ 265 +++ ++ ++++++ 266 ++ ++ +++ +++ 267 ++ ++ +++ +++ 268 ++ + ++ +++ 269 ++ +++ ++++++ 270 +++ +++ +++ +++ 271 +++ ++ +++ +++ 272 +++ +++ +++ +++ 273 ++++++ +++ +++ 274 +++ +++ +++ +++ 275 + + ++ ++ 276 + + +++ ++ 277 +++ ++++ +++ 278 ++ ++ +++ +++ 279 +++ ++ +++ +++ 280 +++ ++ +++ +++ 281 ++ ++++ ++ 282 +++ + +++ +++ 283 +++ + ++ +++ 284 ++ + ++ +++ 285 +++ ++++++ +++ 286 ++ +++ +++ +++ 287 +++ ++ +++ +++ 288 ++ ++ ++ +++ 289 ++ ++++ +++ 290 +++ ++ +++ +++ 291 ++ +++ ++ +++ 292 ++ ++ ++ +++ 293 +++ +++++ +++ 294 + + ++ ++ 295 +++ +++ +++ +++ 296 ++ + +++ ++

The data provided in the present application demonstrate that thecompounds of the invention demonstrate activity in vitro, and may beuseful in vivo in the treatment of cystic fibrosis.

Further benefits of Applicants' invention will be apparent to oneskilled in the art from reading this patent application.

It is to be understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations, or methods, or anycombination of such changes and modifications of use of the invention,may be made without departing from the spirit and scope thereof.

What is claimed:
 1. A pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof,

wherein R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,C(O)OR⁶, and C(O)NR⁷R⁸; R² is C(O)OH or a bioisostere thereof, R^(2A) isselected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, and C₃-C₆ cycloalkyl; R³ is selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein the R³ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; whereinthe R³ C₃-C₆ cycloalkyl, phenyl, and 5-6 membered heteroaryl areoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(3A) is selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl;or R³ and R^(3A), together with the carbon to which they are attached,form a C₃-C₆ cycloalkyl; wherein the C₃-C₆ cycloalkyl formed from R³ andR^(3A) and the carbon to which they are attached is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OH,oxo, CN, NO₂, F, Cl, Br and I; R⁴ is selected from the group consistingof L¹-C₆-C₁₀ aryl, L¹-5-11 membered heteroaryl, L¹-4-12 memberedheterocyclyl, L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl; whereinthe R⁴ C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 memberedheterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹,Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl, Br and I; L¹ is absent, oris selected from the group consisting of C₁-C₆ alkylene, C₂-C₆alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein the L¹C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or as partof a group, are optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkoxy, OH,and oxo; R⁵ is selected from the group consisting of C₆-C₁₀ memberedaryl, 5-11 membered heteroaryl, 4-6 membered monocyclic heterocyclefused to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl;wherein the R⁵ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, 4-6membered monocyclic heterocycle fused to a phenyl group, C₃-C₁₁cycloalkyl, and C₄-C₁₁ cycloalkenyl are optionally substituted with oneor more substituents independently selected from the group consisting ofR¹², OR¹², NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I; R⁶ is selectedfrom the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted withone or more substituents independently selected from the groupconsisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br and I;wherein the R⁶ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸,C(O)OR¹⁸, SO₂R¹⁸, NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I; R⁷ and R⁸are each independently hydrogen or C₁-C₆ alkyl; R⁹, at each occurrence,is independently selected from the group consisting of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆alkynyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R²¹, OR²¹, C(O)R²¹,OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH, oxo, CN, NO₂, F,Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R²⁴, OR²⁴, C(O)R²⁴,OC(O)R²⁴, C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and 5-6 memberedheteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6 membered heteroarylis optionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; R¹², at each occurrence,is independently selected from the group consisting of C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂,OH, oxo, CN, NO₂, F, Cl, Br and I; R¹³ and R¹⁴, at each occurrence, areeach independently hydrogen or C₁-C₆ alkyl; R¹⁵, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁵ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I; R¹⁶ and R¹⁷, at eachoccurrence, are each independently hydrogen or C₁-C₆ alkyl; R¹⁸, at eachoccurrence, is independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; R¹⁹ and R²⁰, ateach occurrence, are each independently hydrogen or C₁-C₆ alkyl; R²¹, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;R²² and R²³, at each occurrence, are each independently hydrogen orC₁-C₆ alkyl; R²⁴, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy- C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; and R²⁵ and R²⁶, at each occurrence, are eachindependently hydrogen or C₁-C₆ alkyl, in combination with apharmaceutically acceptable carrier.
 2. The composition of claim 1,wherein the composition comprises one potentiator, and one or moreadditional correctors.
 3. The composition of claim 1, wherein thecomposition comprises one or more additional therapeutic agents.
 4. Thecomposition of claim 3, wherein the additional therapeutic agents areselected from the group consisting of CFTR modulators and CFTRamplifiers.
 5. The composition of claim 3, wherein the additionaltherapeutic agents are CFTR modulators.
 6. The composition of claim 1,wherein the compound is selected from the group consisting of:rac-(2R,3S,5R)-3-tert-butyl-1-(cyclopentylacetyl)-4-[(2,5-dichlorophenyl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2,5-dichlorophenyl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]oxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-4-[(4,6-dimethoxypyrimidin-2-yl)oxy]-1-[di(propan-2-yl)carbamoyl]-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2R*,3S*,4R*,5R*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2S*,3R*,4S*,5S*)-3-tert-butyl-1-[di(propan-2-yl)carbamoyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-5-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(4,6-dimethoxypyrimidin-2-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-4-[(4-chloro-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-methoxyphenyl)pyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-[2-(dimethylamino)pyridin-3-yl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylicacid;rac-(2R,3S,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(methanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;rac-(2R,3S,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,4R,5R)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(2-methoxyethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-N-(1-methylcyclopropane-1-sulfonyl)-5-phenylpyrrolidine-2-carboxamide;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(cyclopropanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(ethanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(dimethylsulfamoyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-N-(methanesulfonyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxamide;(2R,3S,4R,5R)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2R,3S,4R,5R)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]oxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,4R,5R)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)benzyl)oxy)-1-((1R,3R)-3-methoxycyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-[(1S,3S)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,4R,5R)-3-tert-butyl-1-[(cyclobutyloxy)carbonyl]-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;rac-(2R,3S,4R,5R)-3-tert-butyl-4-[(5-chloro-2-methoxyphenyl)methoxy]-1-[(cyclobutyloxy)carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-2-methoxyphenyl)methoxy]-3-tert-butyl-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(4-methoxy[1,1′-biphenyl]-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclohexyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-[(2-methoxy-5-phenylpyridin-3-yl)methoxy]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(5-cyclopentyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-{[5-(bicyclo[2.2.1]heptan-2-yl)-2-methoxypyridin-3-yl]methoxy}-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(1R,3R)-3-methoxycyclohexane-1-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluoro-4-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-fluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(4-fluoro-2-methylphenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2,4-difluorophenyl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(4-methylphenyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-fluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-fluorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(3-chiorophenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(piperidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoroazetidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(3,3-difluoropyrrolidin-1-yl)-2-methoxypyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(prop-2-en-1-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-phenylpyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-cyclobutyl-5-methoxypyridin-4-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]phenyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-[2-(3,6-dihydro-2H-pyran-4-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-(oxane-4-carbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(3-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(oxane-4-carbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2R)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-cyclobutylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-chlorophenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-cyclopropylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(oxane-4-carbonyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-1-(ethoxycarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-tert-butylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclobutanecarbonyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-3-tert-butyl-1-(cyclopentanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-[2-(difluoromethyl)phenyl]-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4R,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2,6-difluorophenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-cyclopropylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-([1,1′-biphenyl]-2-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2-cyclopropylphenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(2-bromophenyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{[2-methoxy-4-(trifluoromethyl)phenyl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-2-methoxypyridin-3-yl)methoxy]-3-tert-butyl-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[5-(2-cyanopropan-2-yl)-2-methoxyphenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxyquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(4′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrazol-4-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-[3′-(dimethylamino)[1,1′-biphenyl]-2-yl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2′-methyl[1,1′-biphenyl]-2-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyridin-4-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(pyrimidin-5-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-[2-(furan-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(1-methyl-1H-pyrrol-3-yl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[3′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(4′-chloro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-[2-(2H-1,3-benzodioxol-5-yl)phenyl]-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2′-fluoro[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-[2-(6-methoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[4′-(trifluoromethoxy)[1,1′-biphenyl]-2-yl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(4′-cyano[1,1′-biphenyl]-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-{2-[6-(trifluoromethyl)pyridin-3-yl]phenyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-[2-(5-ethoxypyridin-3-yl)phenyl]-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(naphthalen-1-yl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-5-(1-benzofuran-7-yl)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(2-methylpropyl)phenyl]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-(6-methoxypyridine-2-sulfonyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclopropyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-(5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-7-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(3,4-dihydro-2H-pyran-6-carbonyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethoxy)phenyl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)—N-(6-aminopyridine-2-sulfonyl)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-cyclopropylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxamide;(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-3-methoxypyridin-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-({[2-methoxy-5-(trifluoromethyl)pyridin-3-yl](²H₂)methyl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)pyridin-3-yl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(5-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(3-chloro-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[{2-[(²H₃)methyloxy]-5-(trifluoromethyl)phenyl}(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[(5-tert-butyl-2-methoxyphenyl)(²H₂)methyl]oxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-chloro-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-methoxyphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-5-(2-methoxyphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-6,8-dimethylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-8-methylquinolin-3-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(1-methylcyclobutyl)phenyl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,8-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-({2-[2-methoxy-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}oxy)-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(2-methoxy-5,7-dimethylquinolin-3-yl)methoxy]-1-{[(propan-2-yl)oxy]carbonyl}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-[(2-methoxyquinolin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-1-(cyclohexanecarbonyl)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-{[(propan-2-yl)oxy]carbonyl}-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-(2-methoxypropan-2-yl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2,3-dihydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxoethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-{[(1,1,1-trifluoropropan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2R)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{2-hydroxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{2-methoxy-2-[2-methoxy-5-(trifluoromethyl)phenyl]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-3-(2-methoxypropan-2-yl)-1-[(2S)-oxane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{(2R)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{(2S)-2-[2-methoxy-5-(trifluoromethyl)phenyl]propoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopropane-1-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[1-(trifluoromethyl)cyclopentane-1-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-5-phenyl-1-{[(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-({3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-yl}oxy)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-4-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methoxy}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-4-{3-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]propoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(5-iodo-2-methylphenyl)-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1R,2R)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}-1-[(1S,2S)-2-(trifluoromethyl)cyclohexane-1-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{2-[(5-chloro-2-methoxypyridin-3-yl)oxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-tert-butyl-2-methoxyphenyl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-[2-(²H₃)methylphenyl]-1-[(2S,3S)-(2,3-²H₂)oxane-2-carbonyl](2-²H)pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-1-(cyclohexanecarbonyl)-4-{[2-methoxy-5-(1-methylcyclopropyl)pyridin-3-yl]methoxy}-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{2-[2-methoxy-5-(trifluoromethyl)phenoxy]ethoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-4-[(5-bromo-1-benzofuran-2-yl)methoxy]-3-tert-butyl-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(6-tert-butyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]-4-{[7-(trifluoromethyl)-1-benzofuran-2-yl]methoxy}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-chloro-1-benzofuran-2-yl)methoxy]-5-(2-ethylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(naphthalene-1-sulfonyl)-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-2-methoxypyridin-3-yl)methoxy]-1-(cyclohexanecarbonyl)-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; and(2S,3R,4S,5S)-3-tert-butyl-4-[(5-cyclobutyl-1-benzofuran-2-yl)methoxy]-1-[(2S)-oxane-2-carbonyl]-5-{2-[(propan-2-yl)oxy]pyridin-3-yl}pyrrolidine-2-carboxylicacid.
 7. The composition of claim 1, wherein the compound is selectedfrom the group consisting of: (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid; and (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid.
 8. The composition of claim 1, wherein the compound is either(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 9. The compositionof claim 1, wherein the compound is(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 10. The compositionof claim 1, wherein the compound is(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 11. The compositionof claim 1, wherein the compound is(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 12. Apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (III), or a pharmaceutically acceptable saltthereof,

wherein R¹ is selected from the group consisting of SO₂R⁶, C(O)R⁶,C(O)OR⁶, and C(O)NR⁷R⁸; R⁴ is selected from the group consisting ofL¹-C₆-C₁₀ aryl, L¹-5-11 membered heteroaryl, L¹-4-12 memberedheterocyclyl, L¹-C₃-C₁₁ cycloalkyl, and L¹-C₄-C₁₁ cycloalkenyl; whereinthe R⁴ C₆-C₁₀ aryl, 5-11 membered heteroaryl, 4-12 memberedheterocyclyl, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, C(O)OR⁹, C(O)NR¹⁰R¹¹, SR⁹, NR¹⁰R¹¹,Si(R⁹)₃, SF₅, SO₂R⁹, OH, oxo, CN, NO₂, F, Cl, Br and I; L¹ is absent, oris selected from the group consisting of C₁-C₆ alkylene, C₂-C₆alkenylene, C₂-C₆ alkynylene, and C₁-C₆ alkylene-O—; wherein the L¹C₁-C₆ alkylene, C₂-C₆ alkenylene, and C₂-C₆ alkynylene, alone or as partof a group, are optionally substituted with one or more substituentsindependently selected from the group consisting of C₁-C₆ alkoxy, OH,and oxo; R⁵ is selected from the group consisting of C₆-C₁₀ memberedaryl, 5-11 membered heteroaryl, 4-6 membered monocyclic heterocyclefused to a phenyl group, C₃-C₁₁ cycloalkyl, and C₄-C₁₁ cycloalkenyl;wherein the R⁵ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, 4-6membered monocyclic heterocycle fused to a phenyl group, C₃-C₁₁cycloalkyl, and C₄-C₁₁ cycloalkenyl are optionally substituted with oneor more substituents independently selected from the group consisting ofR¹², OR¹², NR¹³R¹⁴, OH, oxo, CN, NO₂, F, Cl, Br and I; R⁶ is selectedfrom the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R⁶ C₁-C₆alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted withone or more substituents independently selected from the groupconsisting of R¹⁵, OR¹⁵, SR¹⁵, NR¹⁶R¹⁷, OH, CN, NO₂, F, Cl, Br and I;wherein the R⁶ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹⁸, OR¹⁸, C(O)R¹⁸, OC(O)R¹⁸,C(O)OR¹⁸, SO₂R¹⁸, NR¹⁹R²⁰, OH, oxo, CN, NO₂, F, Cl, Br and I; R⁷ and R⁸are each independently hydrogen or C₁-C₆ alkyl; R⁹, at each occurrence,is independently selected from the group consisting of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆alkynyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R²¹, OR²¹, C(O)R²¹,OC(O)R²¹, C(O)OR²¹, C(O)NR²²R²³, SO₂R²¹, NR²²R²³, OH, oxo, CN, NO₂, F,Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R²⁴, OR²⁴, C(O)R²⁴,OC(O)R²⁴, C(O)OR²⁴, SO₂R²⁴, NR²⁵R²⁶, OH, oxo, CN, NO₂, F, Cl, Br and I;R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁-C₆ alkyl, phenyl, and 5-6 memberedheteroaryl; wherein each R¹⁰ and R¹¹ phenyl and 5-6 membered heteroarylis optionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; R¹², at each occurrence,is independently selected from the group consisting of C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R¹² 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, N(C₁-C₆ alkyl)₂,OH, oxo, CN, NO₂, F, Cl, Br and I; R¹³ and R¹⁴, at each occurrence, areeach independently hydrogen or C₁-C₆ alkyl; R¹⁵, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹⁵C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I; R¹⁶ and R¹⁷, at eachoccurrence, are each independently hydrogen or C₁-C₆ alkyl; R¹⁸, at eachoccurrence, is independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; wherein each R¹⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; R¹⁹ and R²⁰, ateach occurrence, are each independently hydrogen or C₁-C₆ alkyl; R²¹, ateach occurrence, is independently selected from the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12membered heterocyclyl; wherein each R²¹ C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;R²² and R²³, at each occurrence, are each independently hydrogen orC₁-C₆ alkyl; R²⁴, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy- C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 memberedheteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 memberedheterocyclyl; and R²⁵ and R²⁶, at each occurrence, are eachindependently hydrogen or C₁-C₆ alkyl.
 13. The composition of claim 12,wherein the composition comprises one potentiator, and one or moreadditional correctors.
 14. The composition of claim 12, wherein thecomposition comprises one or more additional therapeutic agents.
 15. Thecomposition of claim 14, wherein the additional therapeutic agents areselected from the group consisting of CFTR modulators and CFTRamplifiers.
 16. The composition of claim 14, wherein the additionaltherapeutic agents are CFTR modulators.
 17. The composition of claim 12,wherein the compound is selected from the group consisting of:(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2R)-oxolane-2-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid;(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid; and (2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid.
 18. The composition of claim 12, wherein the compound is either(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3S)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(3R)-oxolane-3-carbonyl]-5-[2-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 19. The compositionof claim 12, wherein the compound is(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-1-[(2S)-oxolane-2-carbonyl]-5-[3-(propan-2-yl)phenyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 20. The compositionof claim 12, wherein the compound is(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxolane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 21. The compositionof claim 12, wherein the compound is(2S,3R,4S,5S)-3-tert-butyl-4-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy}-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.